Acetic acid type compounds



United States Patent 9 US. Cl. 260-469 12 Claims ABSTRACT OF THEDISCLOSURE The invention relates to p-cycloalkyl substituted phenylacetic acids, esters, amides, aldehydes, alcohols, acetals, ethers, andnon-toxic salts thereof. These compounds possess potentanti-inflammatory properties.

This application is a continuation-in-part of our parent application,Ser. No. 375,307, filed June 15, 1964, now abandoned.

This invention relates to new phenyl aliphatic acids, aldehydes,alcohols, and derivatives thereof. More specifically, this inventionrelates to a p-cycloalky-l or p-lower alkyl-m-substituted phenyl aceticacid and the esters and amides thereof as well as to the correspondingaldehydes, alcohols, acetals, ethers, and non-toxic salts thereof. Morespecifically also, this invention relates to compounds described by theformula:

in which:

R may be cyclohexyl, cyclopentyl, or lower alkyl;

R may be halogen, lower alkoxy, trihalomethyl, lower alkylthio,mercapto, amino, di(lower alkyl)amino, cyano, nitro, carboxamido, loweralkanoylamino, lower alkylsulfonyl, di(lower alkyl)sulfamyl, andhydroxy, at least one of said R being in the meta position;

R,,, is hydrogen;

RG2 is lower alkyl, and when taken together, R,, and

R are methylene or ethylidene; and

X may be COOH; COOR, where R may be lower alkyl, lower alkenyl, loweralkynyl, cyclo lower alkyl, phenyl, lower alkanoylaminophenyl,carboxyphenyl, carboxamidophenyl, lower alkoxy lower alkyl, cyclo loweralkoxy lower alkyl, poly lower alkoxy lower alkyl, poly hydroxy loweralkyl, di(lower alkyl)amino lower alkyl, and cyclo lower alkylaminolower alkyl;

CONH ;CON CON Where Y may be lower alkyl, hydroxy lower alkyl, polyhydroxy lower alkyl, phenyl lower alkyl, phenyl, lower alkoxyphenyl,halogenophenyl, trifiuoromethylphenyl, cyclohexyl, carbobenzyloxymethyl,carboxymethyl, l-carboxyl-3-carbamyl-propylamino, N-diloweralkyl-carboxamidomethyl, N-dilower-alkylamino lower alkyl,N-lower-alkyl-pyrrolidyl, N-lower-alkylpyrrolidyl-lower-alkyl, or Y mayform a heterocyclic group with the nitrogen when Y is the group p Ce CHOH; CH OR Where R is alkyl; CHO; CH(OR) Where R is alkyl; thepharmaceutically non-toxic salts may be the ammonium, alkali and alkaliearth, amine, magnesium, aluminum iron salts, and the like.

In its more narrow aspects, this invention relates to compounds whereinthe 3-position is substituted with an R group. In addition, thetrihalomethyl group indicated in R may only be placed on the 3-positionof the phenyl ring. The above-mentioned aspects of this invention applyequally to compounds wherein X is as previously defined.

In the more preferred aspects of this invention, X is represented by acarboxyl group, R by a cyclohexyl group, R by hydrogen, and R by methyl,or R and R taken together by methylene. R is represented by the groupspreviously mentioned (especially halogen) and restricted to the3-position of the phenyl ring.

The development of antiinflammatory compounds in the past two decadeshas seen the growth of a great many new drugs. Most of these have beensteroids of the ll-oxygenated pregnane series. These, while highlyeffective, have the drawback of causing many side effects. There is aneed in the market for equally effective compounds of much simplerstructure and having less side effects.

We have found that the compounds described above are potentantiinflammatory agents. The compounds specifically are substitutedphenyl acetic acids or the corresponding salts, esters, alcohols,aldehydes, acetals, or ethers which have certain groups in thep-position and are further substituted by a group in the m-position andsubstituents on the a-carbon of the side chain.

The compounds of this invention have a high degree of antiinflammatoryactivity and are eifective in the prevention and inhibition of granulomatissue formation. Certain of them possess this activity in high degreeand are of value in the treatment of arthritic and dermatologicaldisorders and in like conditions which are responsive to treatment withantiinflammatory agents. In addition, the compounds of this inventionhave a useful degree of antipyretic and analgesic activity and alsoindicate some fatty acid synthesis inhibition. For these purposes, theyare normally administered orally in tablets or capsules, the optimumdosage depending, of course, on the particular compound being used andthe type and severity of the condition being treated. Although theoptimum quantities of these compounds of this invention to be used insuch manner will depend on the compound employed and the particular typeof disease condition treated, oral dose levels of preferred compounds inthe range of 1.02,000 mg. per day are useful in control of arthriticconditions, depending on the activity of the specific compound and thereaction sensitivity of the patient.

Since the phenyl acetic acid compounds of the invention possessasymmetric carbon atoms, they are ordinarily present in the form of aracemic mixture. The resolution of such racemates can be carried out bya vast number of known methods. Thus, some racemic mixtures can beprecipitated as eutectics instead of mixed crystals and can thus bequickly separated and in such cases can sometimes be selectivelyprecipitated. The more common method of chemical resolution is, however,greatly preferred. By this method diastereomers are formed from theracemic mixture by reaction with an optically-active resolving agent.Thus, an optically-active base can be reacted with the carboxyl group.The difference in solubility between the diastereomers formed permitsthe selective crystallization of one form and regeneration of theopticallyactive acid from the mixture. There is, however, a third methodof resolving which shows great promise. This is one or the other formsof biochemical procedures using selective enzymatic reaction. Thus, theracemic acid can be subjected to an asymmetric oxidase or decarboxylasewhich will, by oxidation or decarboxylation, destroy one form, leavingthe other form unchanged. Even more attractive is the use of ahydrolysase on a derivative of the racemic mixture to formpreferentially one form of the acid. Thus, esters or amides of the acidscan be subjected to an esterase which will selectively saponify oneenantiomorph and leave the other unchanged.

When the free acid is resolved into (d) and (l) enantiomorphs, theantiinflammatory activity is found to reside virtually completely in the(d) isomer. The desired (d) isomer of the free acid may be prepared byany one of the preceding described resolving methods, preferably workingfrom the free acid as the starting material. For example, amide or saltdiastereomers of the free acid may be formed with optically-activeamines, such as quinine, brucine, cinchonidine, cinchonine,hydroxyhydrindamine, methylamine, morphine, a-phenylethylamine,phenyloxynaphthylmethylamine, quinidine, l-fenchylamine, strychnine,basic amino acids such as lysine, arginine, amino acid esters, and thelike. Similarly, ester diastereomers of the free acid may be formed withoptically-active alcohols, such as borneol, menthol, 2-octano1 and thelike. Especially preferred is the use of cinchonidine to give thereadily decomposable diastereomer salt which may then be resolved bydissolving in a solvent, such as acetone, and distilling the solvent atatmospheric pressure until crystals begin to appear and furthercrystallization produced by allowing the mixture to cool to roomtemperature, thereby separating the two enantiomorphs. The (d) acid maythen be recovered from the (d) salt by extracting the salt between aninorganic solvent, such as petroleum ether, and dilute hydrochloricacid.

Derivatives of the resolved (d) form of the free acid then may beprepared in the usual way. These derivatives generally are more activethan racemates of the same compounds. Consequently, the (d) form ofthese compounds, substantially free of the (1) form, is a still furtheraspect of this invention.

The compounds of this invention are prepared from either an acetophenone(or propiophenone) (hereinafter both called ketone) starting materialcompound of the formula:

All of the starting materials with the exception of m-trihalomethylsubstituent are prepared by nitrating the o,m-unsubstituted ketone andsubsequently converting the nitro ketone compounds to the desired Rsubstituents. It is to be understood, however, that the conversion ofthe nitro group may also be accomplished at various stages along the waytoward producing the final compound. For example, when a 3-substitutedcompound is desired, 3-nitro ketone compound (prepared by nitration ofthe unsubstituted ketone) is converted, when desired, to thecorresponding 3-R substituents by appropriate reactions. For example,the nitro compound is reduced in the presence of palladium under anatmosphere of hydrogen 4 to form the 3-amino compound. This aminocompound may be reacted with an organic halide, such as methyl iodide,to form the mono and disubstituted amino compound or acylated to form a3-alkanoylamino compound. The amino compound may be diazotized and thediazo replaced by a hydroxyl group, which in turn may be alkylated toform a 3-lower alkoxy compound. The diazonium salt derived from theamino compound may also be treated with ethyl xanthate followed bysaponification of the xanthate under alkaline conditions to give themercapto compound, which may, if desired, then be alkylated with adialkylsulfate or alkyl halide to the alkylmercapto compound. Also, thediazonium compound may be reacted with a cuprous halide in the coldunder acid conditions to form the 3-halide compound or reacted withcuprous cyanide to form a 3-cyano compound, which may then be subjectedto alkaline saponification to form a 3-aminocarbonyl compound.

When it is desired to obtain more than one R group on the phenyl moiety,another procedure is used. For example, the ketone is nitrated in the3-position, reduced to the corresponding 3-amino compound and acylated(i.e., acetic anhydride) to the 3-acylamido compound. At this point the3-acylamido compound is again nitrated (i.e., using fuming nitric andconcentrated sulfuric acid) to yield a mixture of the 3-acylamido5'-nitro, 3-acylamido- 2-nitro and 3-acylamido-6-nitro ketone compounds.These isomers are then separated by chromatography. Each of theseisomers may then be hydrolyzed to give the corresponding 3-amino group,which may be further reacted as previously indicated to yield thedesired 3-substituent. Alternatively, the 3-acylamido may remain and thenitro substituent reacted as previously described to yield the desired2,5, or 6 substituted compound. Similarly, the 3- acylamido and nitrogroups may be reacted in any desired order to obtain the varioussubstituent desired on the 3,5, 2,3 and 3,6 positions of the ketonemoiety. Furthermore, the above reaction may be carried out at any othersuitable step along the synthesis of the final compounds.

Many of the ketones may be prepared by a variety of other procedures,some of which may be illustrated as follows:

mQ-t'Lm (or Et) A Friedel-Crafts reaction of benzene with an R halide toobtain an R benzene compound and an additional Friedel-Crafts reactionusing the said R benzene compound and a lower alkyl acid chloride toform a p-substituted R ketone. The ketone is then placed in concentratedsulfuric acid maintained below room temperature and the resultingsolution reacted with fuming nitric acid or the ketone reacted directlywith fuming nitric acid to form the 3-nitro-4-R ketone. The 3-nitroketone compound may then be converted to the desired R as described onpages 8 and 9 infra.

1 halogen The 3-nitro ketone compound obtained from A. above is placedin an inert solvent, such as ethanol-dioxane, and reduced with platinumoxide at room temperature under an atmosphere of hydrogen. The solutionis then treated with gaseous hydrogen chloride and the amine salt thusobtained is placed in a solution of concentrated hydrochloric acid inwater and maintained at below ambient temperatures. A solution of sodiumnitrite is then added followed by a solution of cuprous chloride and thereaction mixture stirred to obtain a 3-chloro ketone compound. The3-cloro compound is then nitrated at the 6-position as previouslydescribed in A. to obtain a 3-chloro-6-nitro ketone compound, which, ifdesired, may be reacted as similarly described on pages 8 and 9 infra.to the 2-R 5- halo keto compounds.

A solution of 4-bromo-2,6-dichloro aniline in benzene and amyl nitriteis refluxed for several hours to obtain 4-bromo-2,6-dichlorobiphenyl.This biphenyl compound is then placed in a glacial acetic acid andreduced at room temperature under an atmosphere of hydrogen withplatinum oxide to yield 4-cyclohexyl-3,S-dichlorobromobenzene. Thisbromobenzene compound is then added to a solution containing magnesiumtumings. The solution is then stirred for a while and acetaldehyde (orpropionaldehyde) is added and the mixture again refluxed for a shortperiod of time to obtain methyl (or ethyl)-(4-cyclohexyl-3,5-dichlorophenyl)-carbinol. This carbinol compound is then treatedwith chromium trioxide in dry pyridine to obtain the4-cyclohexyl-3,5-dichloro ketone compound.

i RpQ-C -Me (or Et) A mixture of 2,3-dichlorobiphenyl and acetic acid isreduced in the presence of platinum oxide under an atmosphere ofhydrogen to obtain 2,3-dichlorophenylcyclohexane. The phenylcyclohexanecompound is then nitrated as in A above to obtain2,3-dichloro-4-nitrophenylcyclohexane. The nitro compound thus obtainedis reduced to the corresponding amine in a mixture of platinum oxide andmethanol. The amine compound thus obtained is heated in a mixture ofconcentrated hydrochloric acid and water. The mixture is then cooled andan aqueous solution of sodium nitrite is added. After stirring for ashort time at low temperatures, cuprous cyanide is added to this mixtureand the mixture is heated for an additional hour to obtain thecorresponding cyano compound. The cyano compound is then placed in etherto which a solution of methyl magnesium iodide is added and the mixturestirred. Subsequently, the mixture is poured into a solution of ice andconcentrated hydrochloric acid, the ether layer separated, and the etherremoved to obtain the 4-cyclohexyl-2,3-dichloro ketone compound.

Magnesium turnings are added to a solution of o-bromobenzotrifiuoride inether and the reaction mixture refluxed for an hour. A solution ofcyclohexanone (or cyclopentanone or secondarybutyl ketone) in dry etheris added at room temperature at a rate to provide gentle reflux. Themixture is then stirred at room temperature for an additional 16 hours.The mixture is then cooled in an acetone ice bath, hydrochloric acidadded, and the ether layer separated. After removal of the ether, theresidue is treated with phosphorus pentoxide and the mixture heated foran hour. Chloroform is then added to the mixture and the chloroformlayer is separated and the chloroform removed to give a residue. Theresidue is then treated with platinum oxide in methanol and the mixturehydrogenated in an atmosphere of hydrogen to give o-R benzotrifluoride.The benzotrifluoride is then nitrated as indicated in A above to give a2-R -5-nitrobenzotrifluoride. This nitro compound is then converted tothe ketone as indicated in D above.

The ketone compounds which have been prepared as prev1ously describedmay be used as the starting material for the preparation of the desiredacid compounds, and the acid compounds subsequently appropriatelyreacted to form the desired aldehydes, acetals, alcohols, ethers, salts,and esters. Flow Sheet I indicates the sequence of steps required forthe preparation of all the compounds of this invention and thedescription which follows indicates the reactions and reactionconditions necessary to prepare these novel compounds.

Rat] Rat RQ /Ra2 Rp CCOOR Rp C-CONH2 (Rmlm (Rm)12 RQ /Ra2 Q m2 l NO;Equivalents As those previously mentioned, including the appropriaterestrictions.

Reactions and conditions Step l.-Reaction with a cyano compound, such assodium cyanide, potassium cyanide, hydrogen cyanide, lower ketonecyanohydrin, and the like [preferably hydrogen cyanide with an aminesuch as a primary, secondary, or tertiary aliphatic amine (ethylamine,propylamine, diethylamine, and trimethylamine)] in a solvent such aslower alkanols (methanol, ethanol, propanol, and the like), liquidhydrogen cyanide, ether, dioxane, tetrahydrofuran, water, mixtures ofwater and the above organic solvents, lower alkanoic acids (acetic,propionic, and the like), and mixtures of the acids and above solvents,pref erably, however, using liquid hydrogen cyanide as the reactant aswell as the solvent, at any suitable temperature, preferably 45-100 C.,but especially 7585 C., until the reaction is substantially complete.

Step 2.-Reaction by methods well known in the art, such as reactionunder acid conditions. Preferably, reaction with a mineral acid(hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid,and the like, preferably fortified hydrochloric acid) in an inertsolvent, such as lower alkanols (methanol, ethanol, propanol), ether,dioxane, tetrahydrofuran, and the like, preferably employing the acid asthe solvent also, between temperatures of and 50 C., preferably at orbelow ambient temperatures, until the reaction is substantiallycomplete.

Step 3.--Acid or basic reaction by methods well known to the art.Preferably, reaction with aqueous alkali or alkali earth hydroxides,such as sodium, potassium, barium, lithium, and strontium hydroxides, ornon-aqueous alkali and alkali earth hydroxides with lower alkanols(methanol, propanol, and the like), ethylene glycol, and the like,aqueous ammonium hydroxide, organic amines (such as lower aliphaticamines), and the like, preferably aqueous sodium or potassium hydroxide,but especialy concentrated aqueous sodium hydroxide (6-12 N) using theabove aqueous hydroxides as the solvents or lower alkanols as thesolvents, preferably using the aqueous hydroxide reactants as solventsalso, at any desirable temperature (0 C. to reflux), preferably at ornear reflux, until the reaction is substantially complete.

Step 4.--Reduction by means well known to the art, i.e., hydrogenationwith palladium under acid conditions with phosphorus and iodine and thelike. Preferably however, reaction with an acid such as lower aliphaticacids( acetic acid, propionic acid, and the like), aromatic acids,inorganic acids, such as phosphoric acid, hydrochloric acid, and thelike, and with phosphorus and iodine or hydrogen iodine, preferablyphosphorus and iodine, using the above aids as solvents also or inether, dioxane, tetrahydrofuran, and the like, preferably the aboveacids as solvents at any suitable temperature (room temperature to 150C., preferably 100l20 C.) until the reaction is substantially complete.

Step 5.-Acid catalyzed dehydration, or formation of the ester of theu-OH with an organic or inorganic acid, followed by pyrolysis, or basictreatment by methods well known to the art. Preferably, the reaction iscarried out in an acid medium using strong acids such as toluenesulfonicacid, p-nitrobenzenesulfonic acid, benzenesulfonic acid, trichloroaceticacid, a mixture of acetic acid and sulfuric acid, and the like(preferably toluenesulfonic acid) in an inert solvent such as aromaticcompounds (benzene, toluene, xylene, and the like), dioxane,tetrahydrofuran, lower alkanoic acids (acetic acid, propionic acid, andthe like), preferably acetic acid or tetrahydrofuran at elevatedtemperatures (7S-150 C., preferably at or near the reflux temperature ofthe system) until the reaction is substantially complete.

Step 6.-Reduction of an a-alkylidene to the corresponding u-lower alkyl,by methods well known to the art. Preferably, reduction over a catalystsuch as palladium, platinum, or Raney nickel, especially 510% palladiumoxide under moderate hydrogen pressure (5-60 pounds, preferably 40pounds) in an inert solvent such as lower alkanols (methanol, ethanol,butanol, and the like), aromatic compounds (benzene, toluene, xylene,and the like), tetrahydrofuran, dioxane, acetic acid, and the like atany suitable temperature (0 C. to the reflux temperature of the system,preferably at room temperature (in ethanol until the reaction issubstantially complete.

Step 7.-Reduction of an acid to its corresponding aldehyde, by methodswell known to the art. Preferably, reaction with a compound such asthionyl chloride, thionyl bromide, phosphorus pentachloride, phosphoruspentabromide, phosphorus oxychloride, phosphorus oxybromide, and thelike, preferably thionyl chloride, in an inert solvent such as benzene,toluene, xylene, ethers (diethyl ether, dioxane), tetrahydrofuran, andthe like, preferably benzene or toluene at any suitable temperature(room temperature to reflux, preferably at or near the refluxtemperature of the system) until the formation of the acid halide issubstantially complete; preferably subse-,

quent removal of the hydrohalic acid and sulfur dioxide thus formed andreaction of the acid halide with a Rosenmund catalyst such as 5%palladium on B 50 with quinoline or with a tritertiarybutoxy alkali oralkali earth aluminum hydride such as potassium, sodium, and lithiumaluminum hydride and the like, preferably reduction withtritertiarybutoxy alkali and alkali earth aluminum hydrid-es, butespecially tritertiarybutoxy lithium aluminum hydride in an inertsolvent such as benzene, toluene, xylene, ethers (diethyl ether,dioxane, and the like) and tetrahydrofuran, preferably tetrahydrofuranor ether at any suitable temperature C. to room temperature), preferably35 to 15 C., until the reaction is substantially complete.

Step 8.Reduction by methods Well known to the art. For example,reduction with an .alkali or alkali earth aluminum hydride, such aslithium, potassium, sodium, and the like. Preferably 200400% excesslithium aluminum hydride in an inert solvent such as tetrahydrofuran,diethyl ether, and the like, preferably other, at any suitabletemperature (15" C. to reflux, preferably 0 C. to ambient temperature)until the formation of the alcohol salt is substantially completelyfollowed by addition of a material to consume the excess hydride such aswater, lower alkanols, dilute mineral acids (hydrochloric acid,hydrobromic acid, sulfuric acid, and the like), preferably addition ofwater followed by a dilute mineral acid (hydrochloric acid, hydrobromicacid, sulfuric acid, and the like), especially water and dilute sulfuricacid, at any suitable temperature, ambient temperatures preferred, untilthe reaction is substantially complete.

Step 9.Reaction with a lower alkanol under an acid catalyst, by methodswell known to the art. For example, reaction with a strong acid such astoluenesulfonic acid, p-nitrobenzenesulfonic acid, benzenesulfonic acid,trichloroacetic acid, mineral acids (hydrochloric acid, hydrobromicacid, sulfuric acid, and the like), boron trifluoride and the like.Preferably reaction with a catalytic amount of toluenesulfonic acid orconcentrated hydrochloric .acid and with a lower alkanol (methanol,

ethanol, propanol, butanol, and the like, preferably methanol) using thealcohols as solvents or combinations of the alcohols and ethers oraromatic compounds at any suitable temperature C. to reflux, preferablyambient temperatures) until the reaction is substantially complete.

Step 10.-Etherification by methods well known to the art. For example,etherification by using an alcohol, alkyl halide, alkyl sulfate and thelike. Preferably, reaction with a lower alkyl halide and a stronglybasic condensing agent such as sodium hydride, potassium hydride,potassium hydroxide, potassium tertiary butoxide, sodamide, and the like(preferably sodium hydride) and a lower alkyl halide such as methyliodide, propyl iodide, methyl bromide, ethyl bromide, and the like(preferably 50% excess of methyl iodide) in any non-active hydrogensolvent such as aromatic solvents (benzene, toluene, xylene, and thelike), ethers (diethyl ether, dioxane, tetrahydrofuran, and the like),dimethylformamide and the like, preferably dimethylformamide, at anysuitable temperature (050 C., preferably .ambient temperatures) untilthe reaction is substantially complete.

Step 11.Esterification by any methods well known to the art. Preferably,reaction with a strong acid such as hydrochloric acid, sulfuric acid,toluenesulfonic acid, p-nitrotoluenesulfonic acid, benzenesulfonic acidand the like (preferably 13% concentrated sulfuric acid) and with anappropriate alcohol (lower alkanols, ar-lower alkanols and the like;especially a lower alkanol such as methanol or ethanol) using thealcohol as solvent .also or using an inert solvent such astetrahydrofuran, ether, and dioxane at any suitable temperature andtime.

Step 12.Amidation reaction by any method well known to the art.Preferably, reaction with thionyl chloride, thionyl bromide, phosphorusoxychloride, phosphorus oxybromide, phosphorus pentachloride, orphosphorus pentabromide in an inert solvent such as ether, benzene,toluene, xylene, tetrahydrofuran, dioxane, and the like to form the acidhalide, followed by reaction with an excess of the amine at any suitabletemperature (0 C. to room temperature preferred); or reaction withdicyclohexylcarbodiimide and an excess of the amine at any suitabletemperature until the reaction is substantially complete. The amine, maybe ammonia, a lower alkyl amine, .an ar-lower alkyl amine and the like.Preferably however, ammonia or a lower alkyl amine.

Step l3.-Preparation of the acid halide as indicated in Step 12 andreaction of the halide with a lower alkanol to form an ester followed byreaction of the ester thus obtained with concentrated sulfuric acid andfuming nitric acid, then saponification of the nitro ester to the freeacid.

In Step 1 when it is desired to employ the cyanide salt, it is necessaryto have the reaction mixture at a pH below 7. This is necessary in orderto have the cyanide salt react as the acid. When the preferred procedureis used, namely, using hydrogen cyanide, the use of an amine, preferablya tertiary amine, is highly preferred, although not absolutelynecessary.

In Step 2, an acid condition is necessary to obtain this reaction, andthose acids as previously indicated may be used. The reaction may be runabove a temperature of 50 C. However, when higher temperatures are used,a mixture of the desired compound as well as the alkylenyl acid isobtained, and it is possible that the reaction may be run attemperatures wherein only the alkylenyl acid compound is obtained.

In Step 4, the reaction may be properly carried out only under acidconditions. A dilute to concentrated acid reaction mixture may beemployed. However, it is preferred to use a concentrated reactionmixture, preferably an aliphatic acid such as acetic acid.

In Step 7, it is preferred to remove the inorganic acid formed after theacid halide preparation; otherwise, the inorganic acid wouldpreferentially consume the subsequent addition of the hydride. However,if it is desired,

the inorganic acid may remain if an excess of the hydride is used toreact with the inorganic acid as well as the acid halide. The preferredhydride in this step is the tritertiarybutoxy lithium aluminum hydride.When this reagent is used, it is preferred to use temperatures below 0C. If temperatures above 0 C. are used, the reduction willpreferentially lead to the corresponding alcohol instead of thealdehyde. As indicated, although higher temperatures may be used, it isnot economically feasible, for a reaction temperature will be reachedwherein the corresponding alcohol will be almost exclusively pro duced.However, if the alcohol is desired, this is still another way of goingdirectly from the acid to the alcohol.

In Step 8, in the preferred reaction almost any solvent could be used,as long as it is inert to the hydride (nonactive hydrogen solvent) andthe respective reactants have some degree of solubility in the solvent.The acid is used in this step to convert the salt of the alcohol to thefree alcohol. The excess hydride is conveniently removed for isolationpurposes by either treating the reaction mixture with an active hydrogencompound, such as water, or by converting the salt to the alcohol andconsumption of the hydride in one step by the cautious addition of anexcess of dilute acid.

In Step 9, the quantity of acid employed is not critical as long as theacid used is a strong acid so as to catalyze the reaction. This reactionmay also be carried out by employing the aldehyde and the appropriatelower alkyl orthoformate. When it is desired to isolate the acetalformed in this step and water is to be used in the isolation procedure,the reaction mixture must be neutralized with a compound such as sodiumcarbonate so as to prevent the hydrolysis of the acetal back to thealdehyde.

In Step 10, in the preferred reaction the yield will be affected by theamount of halide used; therefore, it is preferred to use an excess ofthe halide. In addition, the reaction mixture should not containcompounds with active hydrogens. Therefore, if an active hydrogensolvent from the previous step is present, such as alcohols, it musteither be removed prior to the hydride addition or sufiicient hydrideused to first react with the active hydrogen compound and then be usedfor the desired reaction. However, it is preferred to first remove anyactive hydrogen solvent before proceeding with this step.

In Step 11, the acid may be esterified by any known means. In thisreaction step, the alcohol used for esterification is normally used asthe solvent also. However, when the alcohol is not suitable for use as asolvent, inert solvents are to be used along with the alcohol, aspreviously indicated. When using phenol as the alcohol for theesterification step, it is highly preferred to azeotrope the waterformed so as to allow ester formation. Another highly suitable procedurefor this esterification step is the reaction of the acid with at leastone mole of a diimide (such as dicyclohexylcarbodiimide) and theappropriate alcohol in an inert solvent such as tetrahydrofuran.

In Step 12 where possible, it is preferred to use the amine itself asthe solvent. When this cannot be conveniently done, an inert solvent isused wherein the respeC tive components are fairly soluble. In addition,it is preferred to remove the excess reagent and acidic byproductsformed in this reaction prior to the addition of the amine. However, theacid may be neutralized by using an excess of the desired amine. Step 12may also be carried out as follows: A mixture ofdicyclohexylcarbodiimide, an excess of the amine, and the acid itselfare reacted to produce the amide. The three components are mixed at l0to 50 C. (ambient temperatures preferred) for several hours to obtainthe desired amide.

In Step 13, the reaction may be carried out using concentrated sulfuricacid as the solvent and employing an excess of fuming nitric acid andallowing the reaction to continue at temperatures below roomtemperature, preferably --5 to 5 C., until the reaction is substantiallycomplete. As indicated previously, the nitro ester compound is formed inthis step. However, the ester may be converted to any of the otherdesired side chains (such as acid, alcohol, ether, and the like) by thereactions previously mentioned.

In Steps 7 and 9, compounds containing the hydroxy, primary amino, orsecondary amino group are preferably protected in some way. When it isdesired to use either the hydroxy or amino groups, the compound may bebenzylated before reaction Step 7. When Step 7 is carried out, thereduction will not only reduce the acid to the aldehyde, but at the sametime will debenzylate the above-mentioned groups to yield theappropriate hydroxy or amino group.

The following examples are given by way of illustration:

EXAMPLE 1 4-cyclohexyl-3 -nitroacetophenone To 50 cc. of concentratedsulfuric acid at 10 C. is added portionwise 10.0 grams of4-cyclohexylacetophenone. The green-yellow solution is stirred and 10.0cc. of fuming nitric acid (Sp.G. 1.5) is added dropwise. The temperatureof the reaction mixture is maintained at 10 C. throughout the additionand for 1 hour afterwards. The reaction mixture is then poured onto iceand the oil which separates is extracted with (2X 50 ml.) chloroform.The chloroform solution is then washed with water, dried over sodiumsulfate, and concentrated to an orange-yellow oil. Crystallization fromethanol yields 10.5 grams of 4-cyclohexyl-3-nitroacetophenone. M.P. 66-67 C.

When 4-cyclohexylpropiophenone, 4-cyclopentylacetophenone, and4-secondarybutylacetophenone are used in the above example in place of4-cyclohexylacetophenone, there are obtained 4-cyclohexyl 3nitropropiophenone (M.P. 59-60 C.), 4-cyclopentyl-3-nitroacetophenone,and 3-nitro-4-secondarybutylacetophenone respectively.

EXAMPLE 2 3-chloro-4-cyclohexylacetophenone A solution of 9.89 grams(0.04 mole) of 4-cyclohexyl- 3-nitroacetophenone in 250 cc. ethanolcontaining 10 cc. concentrated hydrochloric acid is reacted withhydrogen in the presence of 0.2 gram of platinum oxide. After thetheoretical amount of hydrogen is taken up, the reaction mixture isfiltered and concentrated to an oily solid. This solid is then dissolvedin 100 cc. concentrated hydrochloric acid and 50 cc. of water and cooledto C. to this cooled solution is added with stirring a solution of 3.0grams of sodium nitrite (0.04 mole) in cc. of water. After a period of10 minutes, there is added a solution of 20.0 grams cuprous chloride in100 cc. concentrated bydrochloric acid and 100 cc. of water. Thereaction mixture is stirred overnight and allowed to warm to roomtemperature. The mixture is then poured onto ice and extracted well with(3 X 50 ml.) ether. Th ether extracts are then washed with water, driedover sodium sulfate, and concentrated. The resulting oil ischromatographed on 200 grams of silica gel using benzene-petroleum ether1:1 as eluent to yield 3.6 grams of 3-chloro-4-cyclohexylacetophenone asan oil. The ketone is characterized by means of its2,4-dinitrophenylhydrazone. M.P. 206.5- 207.5 C.

When hydrobromic acid and cuprous bromide are used in place ofhydrochloric acid and cuprous chloride in the above example, there isobtained 3-bromo-4-cyclohexylacetophenone.

When 4-cyclohexyl 3 nitropropiophenone,4-cyclopentyl-3-nitroacetophenone, and 3-nitro 4secondarybutylacetophenone are used in the above example in place of4-cyclohexyl-3-nitroacetophenone, there are obtained3chloro-4-cyclohexylpropiophenone (B.P. 165 C. at 0.65 mm.),3-chloro4-cyclopentylacetophenone, and 3-chloro-4-secondarybutylacetophenone respectively.

12 EXAMPLE 3 3-amino-4-cyclohexylacetophenone To a solution of 24 gramsof 4-cyclohexyl-3-nitroacetophenone in 250 ml. of absolute ethanol isadded /2 gram of platinum oxide. The mixture is then hydrogenated atroom temperature for 1 hour. The product is then dissolved as much aspossible by heating on a steam bath and filtered. The moist cake isdissolved in 500 ml. of hot ethanol and the catalyst is removed byfiltration. After removal of the solvent in vacuo, the product thusobtained is dissolved in ether, extracted with 2 N hydrochloric acid,and recovered by neutralization and extraction of the aqueous layer withether. Additional product may be obtained from the original ether layer,since the hydrochloride salt is ether soluble. The ether extract isdried over sodium sulfate, filtered, and the solvent removed.Recrystallization of the residue from 250 m1. of boiling hexane yields3-amino-4-cyclohexylacetophenone.

When 4-cyclohexyl 3 nitropropiophenone is used in place of4-cyclohexyl-3-nitroacetophenone in the above example, there is obtained3-amino-4-cyclohexylpropiophenone, M.P. 88-89 C.

EXAMPLE 3A 3-acetamido-4-cyclohexylacetophenone A mixture of 25 ml. ofacetic anhydride and 0.01 mole of 3amino-4-cyclohexylacetophenone isheated on the steam bath for 3 hours. The reaction mixture is pouredonto ice-water and after it is stirred for 1 hour, the mixture isfiltered to give 3-acetamido-4cyclohexylacetophenone.

EMMPLE 3B 1) 3-acetamido-4-cyclohexyl-S-nitroacetophenone (2)3-acetamido-4-cyclohexyl-Z-nitroacetophenone (3)3-acetamido-4-cyclohexyl-6-nitroacetophenone To 200 ml. of a solution of5 parts fuming nitric acid and 2 parts of concentrated sulfuric acidwhich has been cooled to 10 to 15 C. is added with stirring over aperiod of 1 hour 0.1 mole of 3-acetamido-4-cyclohexylacetophenone. Thereaction lIl'liXUtI'G is stirred at -10 to 15 C. for one hour after theaddition is completed. The mixture is then poured onto crushed ice andmade alkaline with ammonia. The nitro compounds are then filtered offand dried. Chromatography on 2000 gm. of silica gel and elution withether-petroleum ether (0- 100%) gives:

3-acetamido-4-cyclohexyl-S-nitroacetophenone,3-acetamido-4-cyclohexyl-2-nitroacetophenone, and3-acetamido-4-cyclohexyl-G-nitroacetophenone.

EXAMPLE 3C 3-amino-4-cyclohexyl-S-nitroacetophenone To a refluxingsolution of 0.01 mole of 3-acetamido-4- cyclohexyl-5-nitroacetophenonein 100 ml. of ethanol is added 50 cc. of concentrated hydrochloric acid.The mixture is refluxed for 5 hours after which time 200 cc. of waterare added and the reaction mixture made alkaline with dilute sodiumhydroxide. The reaction mixture is then extracted well with (3x 200 ml.)ether. The combined ether extracts are washed with (3X 50 ml.) water,dried over sodium sulfate and the solvent then removed to give3-amino-4-cyclohexyl-5-nitroacetophenone.

When 3-acetamido-4-cyclohexyl-2 nitroacetophenone and3-acetamido-4-cyclohexyl 6 nitroacetophenone are used in place of3-acetamido-4-cyclohexyl-5-nitroacetophenone in the above example, thereis obtained 3-amino- 4-cyclohexyl-2-nitroacetophenone and3-amino-4-cyclohexyl-6-nitroacetophenone, respectively.

EXAMPLE 3D The procedure of Example 3 is employed using3-acetamido-4-cyclohexyl 5-nitroacetophenone, 3-acetamido-4- 13cyclohexyl-2-nitroacetophenone and3-acetamido-4-cyclohexyl-6-nitroacetophenone obtained from Example 3B inplace of 4-cyclohexyl-3-nitroacetophenone to obtain the corresponding3-acetamido-5-amino 4 cyclohexylaeetophenone,3-acetamido-2-amino-4-cyclohexylacetophenone and 3-acetamido-6-amino-4cyclohexylacetophenone, respectively.

EXAMPLE 4 3-chloro-4-cyclohexylacetophenone A suspension of 10 grams of3-amino-4-cyclohexylacetophenone and 18 ml. of concentrated hydrochloricacid in 16 ml. of Water is heated until the solid dissolves. Thesolution is then cooled to C. (whereupon the hydrochloride precipitates)and 3.24 grams of sodium nitrite and 6 ml. of water is added to thechilled, stirred solution. After the suspension has remained in the icebath for 15 minutes, 13.2 grams of cuprous chloride dissolved in 240 ml.of concentrated hydrochloric acid is added dropwise with vigrousstirring to the chilled mixture. The mixture is then stirred overnightat room temperature. At this point, the reaction mixture is poured into500 grams of ice, the product extracted with (X 200 ml.) ether, and thecombined ether extracts washed successively with water until neutral,500 ml. of 1 N sodium hydroxide, again with the Water until neutral,dried over magnesium sulfate, filtered, and concentrated in vacuo. Theresidue thus obtained is then treated with petroleum ether to yield3-chloro-4-cyclohexylacetophenone.

When 3-amino-4-cyclohexylpropiophenone is used in place of3-amino-4-cyclohexylacetophenone in the above example, there is obtained3-chloro-4-cyclohexylpropiophenone. B.P. 165 C. at 0.65 mm.

Similarly, when the 3-acetamido-5, 2- and 6-amino compounds obtainedfrom Example 3D are used in place of 3-amino-4-cyclohexylacetophenone inthe above example, there are obtained the corresponding 3-acetamido- 5-,2- and 6-chloro compounds, respectively.

EXAMPLE 5 4-cyclohexyl-3-mercaptopropiophenone To 20.3 grams of3-amino-4-cyclohexylpropiophenone in 17.6 cc. of concentratedhydrochloric acid and 30 grams of ice is added 6.5 grams sodium nitritein a small volume of water. The heterogeneous mush that results is thenadded portionwise with stirring during /2 hour to 16.4 grams ofpotassium ethyl xanthate in 21 cc. water heated at 40-45 C. Afterstirring an additional hour during which time a gum precipitates, themixture is cooled and extracted with ether. The ether extract is washedwith water, dilute sodium hydroxide, and water to neutrality. Theextract is then dried and evaporated in vacuo. The residue is trituratedwith ether and the insoluble m-hydroxy by-product is removed. The etheris evaporated in vacuo to give 19.1 grams of the crude m-xan thate. Thecrude m-xanthate is then dissolved in 54 cc. ethanol and while refluxingthe solution, 20.5 grams potassium hydroxide pellets are addedportionwise. After complete addition, the reaction mixture is refluxeduntil a few drops in water gives an almost clear solution. The mixtureis then concentrated to dryness in vacuo. The residue is dissolved inwater and extracted three times with ether to remove the alkaliinsoluble material. The alkaline layer is charcoaled, acidified with 6 Nsulfuric acid and the precipitated oil extracted with ether. The ethersolution is then dried and evaporated in vacuo to give 6.1 grams of4-cyclohexyl-3-mercaptopropiophenone.

When the 3-acetamido-5-, 2- and 6-amino compounds obtained from Example3D are used in place of B-amino- 4-cyclohexylacetophenone in the aboveexample, there are obtained the corresponding 3-acetamido-5-, 2- and 6-mercapto compounds, respectively.

14 EXAMPLE 6 4-cyclohexyl-3-methylmercaptopropiophenone The m-mercaptointermediate obtained from Example 5 is mixed with 60 cc. Watercontaining 1.0 gram of sodium hydroxide. To this suspension is addeddropwise 3.1 cc. of dimethyl sulfate while stirring. The reactionmixture gets warm and after stirring fifteen minutes, an oil forms.After stirring an additional two hours, the mixture is extracted withether, which is washed with water, dried, and evaporated in vacuo. The5.6 grams of residue are dissolved in benzene and added to 168 grams ofsilica gel prepared with benzene. The column is eluted with benzene toyield 4-cyclohexyl-3-methylmercaptopropiophenone.

When the mercapto intermediates of the 3-acetamido compounds obtainedfrom Example 5 are used in place of the mercapto intermediate in theabove example, there are obtained the corresponding 3-acetamido-5-, 2and 6-methylmercapto compounds, respectively.

EXAMPLE 7 4-cyclohexyl-3-methylsulfonylacetophenone A mixture of 0.01mole of 4-cyclohexyl-3-methylthioacetophenone, excess potassiumpermanganate, and 50 ml. of 2.5 N sodium hydroxide is stirred at roomtemperature for 2 hours. To the mixture is then added sufficient ethanolto consume the excess potassium permanganate. The reaction mixture isthen filtered and the filtrate treated with an excess of dilute aqueoushydrochloric acid. The mixture is then filtered and the cake washed with(2x 15 ml.) water to obtain a solid 4-cyclohexyl-3-methylsulfonylacetophenone.

When the 3-acetamido-5-, 2- and 6-methylthio compounds obtained fromExample 6 are used in place of 4-cyclohexyl-3-methylthioacetophenone inthe above example, there are obtained the corresponding 3-acetamido- 5-,2- and 6-methylsulfonyl compounds, respectively.

EXAMPLE 8 a-Methy1-4-cyclohexyl-3-(N,N-dimethylsulfonamido)- phenylacetic acid A solution of 0.1 mole of methyla-methyl-4-cyclohexyl-3-mercaptophenyl acetate in 100 ml. of 1 N sodiumhydroxide solution is treated with a slight excess of potassiumpermanganate. When the oxidation is complete, the manganese dioxide isremoved by filtration, the filtrate is concentrated to a small volume,and the methyl u-methyl-4-cyclohexyl-3-sulfonylphenyl acetate isisolated by acidification with hydrochloric acid. The sulfonyl compoundis thoroughly dried and heated at reflux with excess thionyl chloride.The excess thionyl chloride is removed by distillation, leaving aresidue of methyl amethyl-4-cyclohexyl-3-chlorosulfonylphenyl acetate.To this residue is added a solution of 10-0 ml. of benzene with excessdimethylamine and the mixture stirred for 1 hour. The mixture is washedwith water, dried over sodium sulfate, and evaporated to yield methyla-methyl- 4 cyclohexyl-3-(N,N-dimethylsultonamido)-phcnyl acetate. Asolution of the methyl ester in aqueous ethanol containing 2 equivalentsof sodium hydroxide is allowed to stand at room temperature for 18hours. The mixture is concentrated in vacuo and acidified with dilutehydrochloric acid to yield a-methyl-4-cyclohexyl-3-(N,N-di-methylsulfonamido)-phenyl acetic acid.

When the esters of the 3-acetamido-5-, 2- and 6-mercapto compoundsobtained from Example 47 are used in place ofmethyl-a-methyl-4-cyclohexyl-3-mercaptophenyl acetate in the aboveexample, there are obtained the corresponding 3-acetamido-5-, 2- and6-(N,Ndimethylsulfonamido) acetic acid compounds, respectively.

EXAMPLE 9 5-chloro-4-cyclohexyl-2-nitroacetophenone To cc. ofconcentrated sulfuric acid maintained at -10 to 15 C. is added whilestirring 6.0 grams of 3-chloro-4-cyclohexylacetophenone. There is thenadded dropwise 15 cc. of fuming nitric acid (Sp. G. 1.5), thetemperature being maintained at -15 to 1*0 C. during the addition andfor 1 hour afterward. The reaction mixture is then poured onto ice andextracted well with ether. The combined ether extracts are washed wellwith Water, dried over sodium sulfate, and concentrated to give an oilysolid. The residue is then chromatographed on 500 grams of silica gel.Elution with 10% etherpetroleum ether yields 4.1 grams of5-chloro-4-cyclohexyl-2-nitroacetophenone (M.P. 143144 C.).

When 3-bromo-4-cyclohexylacetophenone is used in place of3-chloro-4-cyclohexylacetophenone in the above example, there isobtained 5-bromo-4-cyclohexyl-Z-nitroacetophenone.

EXAMPLE 10 4-cyclohexyl-2,S-dichloroacetophenone To a solution of 2.81grams of 5-chloro-4-cyclohexyl-2- nitroacetophenone and 50 ml. ofethanol-25 ml. dioxane is added 0.1 gram of platinum oxide and themixture hydrogenated at room temperature. The reaction mixture isfiltered and the filtrate concentrated to an oil. The oil is dissolvedin ether and the resulting solution is cooled and saturated with gaseoushydrogen chloride. The amine salt (2.37 grams) is collected, dried, andthen suspended in a Well-stirred mixture of 50 cc. concentratedhydrochloric acid and 25 cc. of water which has been cooled to to C. Asolution of 0.7 gram sodium nitrite in 15 cc. of water is addeddropwise, and after 15 minutes has elapsed, a solution of 5 gramscuprous chloride in 50 cc. of hydrochloric acid-water (1:1) is added.The reaction mixture is then stirred overnight at room temperature,poured onto ice, and extracted well with (2X 50 ml.) ether. The combinedether extracts are washed well with (2X 25 ml.) water, dried over sodiumsulfate, and concentrated. The resulting oil is chromatographed on 100grams of acidwashed alumina. Elution with 2% ether-petroleum ether gives2.11 grams of colorless 4-cyclohexyl-2,S-dichloroacetophenone (M.P.136-137 C.).

When 5-bromo-4-cyclohexyl 2 nitroacetophenone is used in place of5-chloro-4-cyclohexyl-Z-nitroacetophenone in the above example, there isobtained 5-bromo-2- chloro-4-cyclohexylacetophenone.

When hydrogen bromide, hydrobromie acid, and cuprous bromide are used inplace of hydrogen chloride, hydrochloric acid, and cuprous chloride inthe above example, there is obtained2-bromo-5-chloro-4-cyclohexylacetophenone.

EXAMPLE 11 2,3-dichlorophenylcyclohexane 400 ml. of acetic acidcontaining 11.0 grams platinum oxide is treated with hydrogen under 41lbs. of pressure. When no more hydrogen is taken up, 22.31 grams (0.1mole) of 2,3-dichlorobiphenyl is added, and this mixture is reduceduntil 0.3 mole of hydrogen has been taken up. The reaction mixture isthen filtered and the filtrate concentrated in vacuo. The residue isthen fractionally distilled to yield 11.82 grams of2,3-dichlorophenylcyclohexane. B.P. 124-126 C. at 1.4-1.5 mm.

EXAMPLE 12 2,3-dichloro-4-nitrophenylcyclohexane To 150 cc. concentratedsulfuric acid at 0 to 5 C. is added while stirring 10.0 grams of2,3-dichlorophenylcyclohexane. There is then added dropwise withstirring 10.0 cc. of fuming nitric acid, the temperature of the reactionmixture being kept at 0 to 5 C. throughout the addition. The mixture isthen stirred at 0 C. for 1 hour, poured onto ice, and extracted wellwith (2X 50 ml.) ether. The combined ether extracts are washed with (2X25 ml.) water, dried over sodium sulfate, and con- 16 centrated. Theresidue is chromatographed on 300 grams of silica gel. Elution withether-petroleum ether (IO-70% gives2,3-dichloro-4-nitrophenylcyclohexane.

EXAMPLE 13 1- o-trifluoromethylphenyl -cyclohexanol A solution of 113grams (0.5 mole) of o-bromobenzotrifiuoride in 150 ml. dry ether isadded dropwise to 12.2 grams (0.5 mole) of magnesium turnings in 100 ml.dry ether with stirring. After a few ml. of solution is added, themixture is heated in a hot-water bath until the reaction has started.After complete addition, the reaction mixture mixture is refluxed for 1hour. A solution of 48.8 grams (0.5 mole) of cyclohexanone in 50 ml. dryether is then a-dded at room temperature at a rate to provide a gentlereflux. After complete addition, the reaction mixture is allowed to stirat room temperature overnight. The reaction mixture is then cooled in anacetone-ice bath and 104 ml. of 5 N hydrochloric acid is added dropwisewith stirring. The mixture is stirred an additional /2 hour and theether layer is separated. The acid layer is then extracted with freshether. The ether extracts are combined, washed with water, dried overanhydrous magnesium sulfate, and evaporated in vacuo to yieldl-(o-trifluoromethylphenyl)-cyclohexanol.

EXAMPLE 14 o( l-cyclohexenyl) -benzotrifluoride To the1-(o-trifluoromethylphenyl) -cyclohexanol obtained in Example 13 from113 grams of o-bromobenzotrifiuoride is added 34 grams of phosphorouspentoxide and the mixture heated on a steam bath. After the initialreaction has occurred and subsided, an equal amount of phosphorouspentoxide is added and the mixture is heated on the steam bath for 1hour. The mixture is then distributed between chloroform and water. Thechloroform layer is separated, washed with water, dried over anhydrousmagnesium sulfate, and evaporated in vacuo. The liquid residue isdistilled in vacuo at 8-9 mm., yielding 64.6 grams of theo(l-cyclohexenyl)-benzotrifiuoride. B.P. 100-104 C.

EXAMPLE 15 o( l-cyclohexyl) -benzotrifluoride To 64.0 grams ofo(l-cyclohexenyl)-benzotrifluoride is added 200 ml. of methanol and 1.0gram of platinum oxide. The mixture is then hydrogenated at roomtemperature and 40 p.s.i. After completion of the reaction, the mixtureis filtered and the filtrate evaporated in vacuo. The residual oil thusobtained is distilled at 5-6 mm., yielding 60.8 grams ofo(l-cyclohexyl)benzotrifluoride. B.P. 92-93 C. Calcd. for C H F C,68.40; H, 6.62. Found: C, 68.39; H, 6.92.

EXAMPLE 16 Z-cyclohexyl-S-nitrobenzotrifluoride Ten grams (0.044 mole)of o(1-cyclohexyl)-benzotrifluoride is added dropwise with stirring tograms of Water-cooled fuming nitric acid. The inner temperature of thereaction mixture is maintained at about 16 C. After complete addition,the milky heterogeneous mixture is slowly heated. The mixture becomeshomogeneous at about 40 C. and slight boiling occurs at 5560 C. Afterheating at a maximum temperature of 65 C. for /2 hour, the heat isremoved and stirring is continued for several hours. The mixture becomescloudy again on removal of the heat. The reaction mixture is then pouredinto an ice-water mixture and the mixture is filtered. The cake thusobtained is washed with excess water and air dried. The solid is thenrecrystallized from methanol yielding a total of 8.0 grams of2-cyclohexyl-5-nitrobenzotrifluoride. M.P. 6869 C. Calcd. for C H F NOC, 57.14; H, 5.16. Found: C, 57.24; H, 5.09.

-1 7 EXAMPLE 17 To a solution of 26.6 grams (0.097 mole) of 2-cycl0hexyl-S-nitrobenzotrifluoride in 300 ml. methanol is added 0.6 gramplatinum oxide and the mixture hydrogenated at room temperature and 40p.s.i. The mixture is then filtered and the filtrate concentrated invacuo, yielding 23.6 grams of the crude amine. The liquid residuecrystal lizes on standing several days. The mixture is filtered to yieldsolid S-amino-2-cyclohexylbenzotrifluoride. M.P. 61-63 C.

A sample of the hydrochloride is prepared by dissolving some of theamine in chloroform and shaking with 2.5 N hydrochloric acid. Thechloroform layer is dried and evaporated in vacuo to a crystallineresidue. The solid is triturated with ether and dried in vacuo at roomtemperature. Calcd. for C H F NHCI: C, 55.81; H, 6.13. Found: C, 55.70;H, 6.34.

When (2,3-dichloro-4-nitrophenyl)-cyclohexane is used in place of2-cyclohexyl-5-nitrobenzotrifiuoride in the above example, there isobtained 4-amino-2,3-.dichlorophenylcyclohexane.

EXAMPLE 18 4-cyclohexyl-S-trifluoromethylbenzonitrile A mixture of 23.6grams (0.097 mole) of -amino-2- cyclohexylbenzotrifluoride and 37 ml.concentrated hydrochloric acid in 37 ml. water is heated on the steambath to 80 C., resulting in an insoluble white precipitate. The mixtureis then diluted to a volume of 200 ml. with water and stirred at roomtemperature for /2 hour. The mixture is then cooled to 5 C. and 8.3grams of sodium nitrite in 26 ml. water, cooled in an ice bath, is addeddropwise, keeping the temperature at 5 C. A homogeneous solution isobtained and kept at -5 C.

A solution of 28.6 grams potassium cyanide in 52 ml. of water is addedwith stirring to a hot solution of 23.4 grams cupric sulfate in 95 ml.of water. The diazonium solution is then added in a stream to thissolution while stirring and heating on the steam bath. After completeaddition, the stirring and heating are continued for /2 hour. Thereaction mixture is cooled and extracted with chloroform. The chloroformextract is dried and evaporated in vacuo, yielding 23.7 grams of crudeproduct. This product is then dissolved in petroleum benzen andchromatographed on 711 grams of alkaline alumina, previously washed withacetone and petroleum benzin. The column is eluted with petroleum benzinto give 10.5 grams of crystalline product, M.P. 7375 C. Calcd. for C H FN: C, 66.39; H, 5.57; N, 5.53; F, 22.51. Found: C, 66.67; H, 5.85; N,5.26; F, 21.9.

When (4 amino 2,3-dichlorophenyl)-cyclohexane is used in place ofS-amino-2-cyclohexylbenzotrifluoride in the above example, there isobtained 4-cyano-2,3-dichlorophenylcyclohexane.

EXAMPLE 19 4-cyclohexyl-5-trifluoromethylacetophenone A solution of 10.3grams (0.04 mole) of 4-cyclohexyl- 5-trifluoromethylbenzonitrile in ml.dry ether is added dropwise over a one-hour period to a solution ofmethylmagnesium iodide (prepared from 3.6 ml. methyl iodide and 1.2grams of magnesium in 50 ml. of dry ether). The reaction mixture isstirred overnight. The mixture is then poured into 68 grams of ice and13.5 ml. of concentrated hydrochloric acid. The ether layer isseparated, washed with water, dried over anhydrous magnesium sulfate,and evaporated in vacuo, yielding 10.4 grams of product.

When ethylmagnesium iodide is used in place of methylmagnesium iodide inthe above example, there is obtained4-cyclohexyl-5-trifluoromethylpropiophenone.

When (4 cyano 2,3-dichlorophenyl)-cyclohexane is used in place of4-cyclohexyl-5-trifluoromethylbenzonitrile in the above example, thereis obtained 4-cyclohexyl- 2,3-dichloroacetophenone.

EXAMPLE 20 4-bromo-2,6-dichlorobiphenyl To a solution of 0.05 mole of4-bromo-2,6-dichloroaniline in 200 ml. dry benzene is added 0.07 mole ofamyl nitrile and the resultant mixture heated slowly and carefully toreflux over a period of 1 hour. After refluxing overnight, the mixtureis allowed to cool, extracted with (2X 50 ml.) dilute hydrochloric acidand water, and the benzene solution then dried over anhydrous magnesiumsulfate. To the mixture is then added decolorizing carbon and the entiremixture is filtered. Silica gel (50 grams) is added to the driedfiltrate solution and the mixture concentrated to dryness. The resultantcrude packing is placed on a 500-gram silica gel column and eluted withpetroleum ether, yielding 4-bromo-2,6-dichlorobiphenyl.

Example 21 4-cyclohexyl-3 ,5 -dichlorobromobenzene A solution of 0.004mole of 4-bromo-2,6-dichlorobiphenyl in 20 ml. of glacial acetic acid isreduced with hydrogen at room temperature, 40 psi, in the presence of0.5 gram platinum oxide until 0.012 mole hydrogen is absorbed (theacetic acid-platinum oxide mixture is prereduced). The mixture isfiltered and the filtrate concentrated in vacuo. The oily residue thusformed is taken up in benzene, washed with water, dried over anhydrousma nesium sulfate, filtered, silica gel (5 grams) added, and the mixtureconcentrated to dryness. The crude packing is then placed on a -gramsilica gel column and eluted with petroleum ether, yielding4-cyclohexyl-3,5-dichlorobromobenzene.

Example 22 Methyl-(4-cyclohexyl-3,5-dichlorophenyl)-carbinol A dry2-liter three-necked round-bottomed flask is equipped with a sealedstirrer, a 500-ml. dropping funnel, and an eflicient reflux condenserattached to a calcium chloride tube. To a mixture of 29.1 grams ofmagnesium turnings, a crystal of iodine, and about 50 ml. of dry etheris added a solution of 1.2 moles of4-cyc1ohexyl-3,5-dichlorobromobenzene in 850 m1. of dry ether withstirring at a rate which maintains rapid refluxing (13 hours). Themixture is then stirred and heated on the steam bath under reflux for 1hour after all the 4-cyclohexyl-3,5-dichlorobromobenzene has been added.A cooled solution of 1.4 moles of freshly distilled acetaldehyde in 200ml. of dry other is added over a period of 2-4 hours. The mixture isthen stirred and heated under reflux for 1 hour after the addition iscompleted. The reaction mixture is then cooled in ice, and the additioncompound is decomposed by adding dropwise with stirring ml. of a 25%solution of ammonium chloride in water. The ether solution is thendecanted and dried over anhydrous magnesium sulfate. vAfter removal ofthe ether, the residue is purified by chromatography on a silica gelcolumn (wt./ wt. 50: 1) using ether-petroleum ether (v./v. 2070%) aseluent to obtain methyl (4-cyclohexyl-3,5-dichlorophenyl -carbinol.

Example 23 4-cyclohexyl-3,5-dich1oroacetophenone To a cooled mixture of3.0 grams of chromium trioxide in 30.5 of dry pyridine while maintainingthe temperature of the mixture at 10-15 C. is added dropwise a solutionof 0.0073 mole of methyl-(4-cyclohexyl-3,S-dichlorophenyl)-carbinol in18 ml. dr pyridine. After the addition is complete, the mixture isallowed to warm to and remain at room temperature overnight. The mixtureis then poured onto a stirred ice-water mixture (ca. 300 ml.).

acidified With dilute hydrochloric acid, and extracted with (2X 50 ml.)ether. The combined ether extractions are then Washed with dilutehydrochloric acid, water, and dried over anhydrous magnesium sulfate anddecolorizing carbon. The mixture is then filtered, concentrated to aresidue, and chromatographed on a silica gel column (100 grams) using anether-petroleum ether system (v./v. 10-60% ether-petroleum ether) aseluent to yield 4-cyclohexyl-3 ,5 -dichloro acetophenone.

Example 23A The procedure of example 3C is followed using the 3-acetamido compounds obtained from Examples 3D, 4, 5, 6 and 7 in place of3-acetamido-4-cyclohexyl-S-nitroacetophenone to form the corresponding3-amino compounds.

Example 24 a-I-Iydroxy-a-methyl-3-chloro-4-cyclohexylpheny1 acetamide To2.0 cc. of stirred and cooled liquid HCN is added dropwise 2.37 grams of3-chloro-4-cyclohexylacetophenone followed by 5 drops of piperidine. Thereaction mixture is kept at C. for 1 hour and then poured into 25 cc. ofconcentrated hydrochloric acid which has been cooled to 0 C. The mixtureis then saturated with gaseous hydrogen chloride, stirred 2 hours at 0C., and then stirred overnight at room temperature. The reaction mixtureis then extracted well with (2X 50 ml.) ether. The combined etherextracts are washed with water, dried over sodium sulfate, andconcentrated. The residue is then dried under vacuum and thenrecrystallized from benzenepetroleum ether and benzene-hexane to yield1.2 grams of a hydroxy a-methyl-3-chloro-4-cyclohexylphenyl acetamide.M.P. 161163 C.

When 3-bromo-4-cyclohexylacetophenone,3-ehloro-4-cyclopentylacetophenone,3-chloro-4-secondarybutylacetophenone,4-cyclohexyl-2,S-dichloroacetophenone,2-bromo-S-chloro-4-cyclohexylacetophenone,5-bromo-2-chloro-4-cyclohexylacetophenone,4-cyclohexyl-5-trifiuoromethylacetophenone,4-cyclohexyl-2,3-dichloroacetophenone,4-cyclohexyl-3,S-dichloroacetophenone,3-chloro-4-cyclohexylpropiophenone,4-cyclohexyl-3-trifiuoromethylpropiophenone,4-cyclohexyl-3-nitroacetophenone,5-chloro-4-cyclohexyl-2-nitroacetophenone,4-cyclohexyl-3-methylsulfonylacetophenone, and3-acetamido-2-amino-4-cyclohexylacetophenone,3-acetamido-5-amino-4-cyclohexylacetophenone,3-acetarnido-6-amino-4-cyclohexylacetophenone,3-acetamido-2-chloro-4-cyclohexylacetophenone,3-acetamido-5-chloro-4-cyclohexylacetophenone,3-acetamido-6-chloro-4-cyclohexylacetophenone,3-acetamido-2-mercapto-4-cyclohexylacetophenone,3-acetamido-5-mercapto-4-cyclohexylacetophenone,3-acetamido-6-amino-4-cyclohexylacetophenone,3-acetamido-2-methylmercapto-4-cyclohexylacetophenone,3-acetamido-5-methy1mercapto-4-cyclohexylacetophenone,3-acetamido-6-methylmercapto-4-cyclohexylacetophenone,3-acetamido-2-methylsulfonyl-4-cyclohexylacetophenone,3-acetamido-5-methylsulfonyl-4-cyclohexylacetophenone,3-acetamido-6-methylsulfonyl-4-cyclohexylacetophenone,3-amino-2amino-4-cyclohexylacetophenone,3-amino-5-amino-4-cyclohexylacetophenone,3-amino-6-amino-4-cyclohexylacetophenone,3-amino-2-chloro-4-cyclohexylacetophenone,3-amino-5-chloro-4-cyclohexylacetophenone,3-amino-6-chl0ro-4-cyclohexylacetophenone,3-amino-2-mercapto-4-cyclohexylacetophenone,3-amino-5-mercapto-4-cyclohexylacetophenone,3amino-6-mercapto-4-cyclohexylaeetopheno3-amino-2-methylmercapto-4-cyclohexylacetophenone,3-amino-5-methylmercapto-4-cyclohexylacetophenone,3-amino-6-rnethylmercapto-4-cyclohexylacetophenone,3-amino-2-methylsulfonyl-4-cyclohexylacetophenone,3-amino-5-methylsulfonyl-4-cyclohexylacetophenone,3-amino-6-methy1sulfonyl-4-cyclohexylacetophenone,3-amino-4-cyclohexyl-2-nitroacetophenone,3-amino-4-cyclohexyl-5-nitroacetophenone, and3-amino-4-cyclohexyl-6-nitroacetophenone are used in place of3-chloro-4-cyclohexylacetophenone in the above example, there areobtained u-hydrOXy-u-methyl-B-bromo-4-cyclohexylphenyl acetamide,a-hydrOXy-a-methyLB-chloro-4-cyclopentylphenyl acetamide,a-hydroxy-a-methyl-3-chloro-4-secondarybutylphenyl acetamide,a-hydroxy-a-methyl-4-cyclohexyl-2,S-dichlorophenyl acetamide,ahydroxy-u-methyl-2-bromo-S-chloro-4-cyclohexylphenyl acetamide,a-hydroxy-a-methyl-5-bromo-2-chloro-4-cyclohexylphenyl acetamide,a-hydroxy-u-methyl-4-cyclohexyl-S-trifiuoromethylphenyl acetamide (M.P.97-99 C.), a-hydroxy-a-methyl-4-cyclohexyl-2,3-dichlorophenyl acetamide,whydroxy-a-methyl-4-cyclohexyl-3,S-dichlorophenyl acetamide,a-ethyl-u-hydroxy-3-chloro-4-cyclohexylphenyl acetamide (M.P. 158-159C.), a-ethyl-a-hydroxy-4-cyclohexyl-3-trifluoromethylphenyl acetamide,a-hydroxy-a-rnethyl-4-cyclohexyl-3-nitrophenyl acetamide,u-hydroxy-a-methyl--5-chloro-4-cyclohexyl-2-nitrophenyl acetamide,u-hydroxy-a-methyl-4-cyclohexyl-3-methylsulfonylpheny acetamide, anda-hydroxy-a-methyl-3-substituted, 2-, 5- and 6 substituted 4cyclohexylphenyl acetamide compounds, respectively.

EXAMPLE 25 a-Hydroxy-a-methyl-3-amino-4-cyclohexylphenyl acetamide To asolution of 0.12 mole of a-hydroxy-a-methyl- 4-cyclohexyl-3-nitrophenylacetamide in 250 ml. of absolute alcohol is added 0.5 gram of platinumoxide. The mixture is hydrogenated at room temperature for 1 hour. Theproduct is then dissolved as much as possible by heating on a steam bathand filtered. The moist cake is dissolved in 500 ml. of hot ethanol andthe catalyst is removed by filtration. After removal of the solvent invacuo, the product is dissolved in ether, extracted with 2 Nhydrochloric acid, and recovered by neutralization and extraction of theaqueous layer with ether. The ether extract is then tried over sodiumsulfate, filtered, and the solvent removed to obtain a residue ofa-hydroxyu-methyl-3-amino-4-cyclohexylphenyl acetamide.

When whydroxy-a-methyl-5-chloro-4-cyclohexyl-2-nitrophenyl acetamide isused in place of a-hydroxy-amethyl-4-cyclohexyl-3-nitrophenyl acetamidein the above example, there is obtained a-hydroxy-a-methyl-2-amino-5-chloro-4-cyclohexylphenyl acetamide.

Similarly, when the 2-, 5- and 6-nitrophenyl acetamide compoundsobtained from Example 24 are used in place of the a hydroxy ccmethyl-4-cyclohexyl-3-nitrophenyl acetamide in the above example, thereare obtained the corresponding a-hydroxy-a-methyl-2-, 5- and 6-aminoacetamide compounds.

EXAMPLE 26 u-Hydroxy-a-methyl-3-chloro-4-eyclohexylphenyl acetic acid 210.88 grams of a-hydroxy-a-methyl-3-chloro-4-cyclohexylphenyl acetamideis refluxed overnight in 20 cc. of ethanol-Water 1:1 containing 1.0 gramof sodium hydroxide. There is added 40 cc. Water and the reactionmixture is heated to remove the ethanol. The aqueous alkaline 5 va-hydroxy-a-methyl-3-chloro-4-cyclopentylphenyl acetamide,a-hydroxy-a-methyl3 -chloro-4-secondarybutylphenyl acetamide,a-hydroxy-o-methyl-4-cyclohexyl-Z,S-dichlorophenyl acetamide,a-hydroxy-a-methyl-2-bromo-5-chloro-4-cycl0hexylphenyl acetamide,a-hydroxy-a-methyl-5-bromo-2-chloro-4-cyclohexylpheny1 acetamide,u-hydroxy-a-methyl-4-cycl0hexyl-5-trifluoromethylphenyl acetamide,whydroxy-a-methyl-4-cyclohexyl-2,3-dichlorophenyl acetamide,u-hydroxy-a-methyl-4-cyclohexyl-3,S-dichlorophenyl acetamide,a-ethyl-u-hydroxy-3-chloro-4-cyclohexylphenyl acetamide,a-ethyl-u-hydroxy-4-cycl0hexyI-S-trifluoromethylphenyl acetamide,a-hydroxy-a-methyl-4-cyclohexyl-3-nitrophenyl acetamide,a-hydroxy-u-methyl-5-chloro-4-cyclohexyl-Z-nitrophenyl acetamide,a-hydroxy-a-methyl-3-amino-4-cyclohexylphenyl acetamide,a-hydroxy-a-methyl-Z-amin-5-chloro-4-cyclohexylphenyl acetamide,a-ethyl-a-hydroxy-3-amino-4-cyclohexylphenyl acetamide,a-hydroxy-u-methyl-4-cyclohexyl-3-methylsulfonylphenyl acetamide,

the a-hydroxy-u-methyl-Zs-substituted, 2-, and6-substituted-4-cyclohexylphenyl acetamide compounds obtained fromExample 24 and the a-hydroxy-a-methyl-2-, 5- and G-amino acetamidecompounds obtained from Example 25 are used in place ofa-hydroxy-a-methyl-Ii-chloro-4-cyclohexylphenyl acetamide in the aboveexample, there are obtaineda-hydroxy-a-methyl-3-bromo-4-cyclohexylphenyl acetic acid,a-hydroxy-a-methyl-3-chloro-4-cyclopentylphenyl acetic acid,u-hydroxy-u-methyl-3-chloro-4-secondarybutylphenyl acetic acid,a-hydroxy-a-methyl-4-cyclohexyl-2,5-dichlorophenyl acetic acid,a-hydroxy-u-methyl-2-bromo-5-chloro-4-cyc1ohexylphenyl acetic acid,a-hydroxy-a-methyl-5-bromo-2-chloro-4-cyclohexylphenyl acetic acid,a-hydroxy-a-methyl-4-cyclohexyl-S-trifluoromethylphenyl acetic acid,u-hydroxy-a-methyl-4-cyclohexyl-2,3-dichlorophenyl acetic acid,ot-hydroxy-a-methyl-4-cyclohexyl-3,S-dichlorophenyl acetic acid,a-ethyl-a-hydroxy-3-chloro-4-cyclohexylphenyl acetic acid (M.P.134.5135.5 C.),

u-ethyl-a-hydroxy-4-cyclohexyl-5-trifluor0methy1phenyl acetic acid (M.P.122 C.), a-hydroxy-a-methyl-4-cyclohexyl-3-nitrophenyl acetic acid,a-hydroxy-a-methyl-5-chloro-4-cyclohexyl-2-nitrophenyl acetic acid,a-hydroxy-a-methyl-S-amino-4-cyclohexy1phenyl acetic acid,a-hydroxy-a-methyI-Z-amino-5-chloro-4-cyclohexylphenyl acetic acid,a-ethyl-a-hydroxy--amino-4-cyclohexylphenyl acetic acid,u-hydroxya-methyl-4-cyclohexyl-3-methylsulfonylphenyl acetic acid,

a the a-hydroxy-u-methyl-3-substituted, 2-, 5- and6-substituted-4-cyclohexylpheny1 acetic acids and theu-hydroxya-methyl-2-, 5- and 6-amino acetic acid compounds,respectively.

EXAMPLE 27 a-Ethyl-a-hydroxy-4-cyclohexy1-S-hydroxyphenyl acetic acid To2.6 grams (0.01 mole) of a-ethyl-a-hydroxy-3- amino-4-cyclohexylphenylacetic acid suspended in 50ml. of Water is added 2.0 ml. of concentratedsulfuric acid. The resulting suspension of the sulfate salt is cooled to5 C., and a solution of 0.7 gram (0.011 mole) of sodium nitrite in 10ml. of water is added slowly. The solution of diazonium salt is heatedat 65 C. until evolution of nitrogen ceases; it is then cooled andextracted with ether. The ethereal solution is washed with water, driedover magnesium sulfate, treated with charcoal, filtered, andconcentrated to approximately 10 ml. Addition of 1-2 volumes of hexanecauses the a-ethyl-a-hydroxy-4-cyclohexyl-3-hydroxyphenyl acetic acid tocrystallize: 1.7 grams, M.P. -166 C.

When the a-hydroxy-a-methyl-2-, 5- and 6-amino acetic acid compoundsobtained from Example 26 are used in place of aethyl-a-hydroxy-3-amino-4-cyclohexylphenyl acetic acid in the aboveexample, there are obtained the corresponding a-hydroxy-a-methyl-2-, 5-and 6-hydr0xy acetic acid compounds.

EXAMPLE 28 a-Ethyl-a-hydroxy-4-cyclohexyl-3-fluorophenyl acetic acid Asolution of 2.6 grams (0.01 mole) ofa-ethyl-ahydroxy-3-amino-4-cyclohexylphenyl acetic acid in 5 ml. oftetrahydrofuran is added to a solution of 10 ml. of 50% fluoboric acidin 5 ml. of water. The clear solution is cooled to 5 C. and isdiazotized with 1.4 grams (0.02 mole) of sodium nitrite in 4 ml. ofwater. After the addi tion of 10 ml. of 50% fluoboric acid, thesupernatant is decanted from the oily diazonium compound. The latter iswarmed with 30 ml. of toluene on the steam bath until evolution ofnitrogen ceases. The cooled mixture is extracted with dilute sodiumhydroxide solution. The alkaline solution is treated with charcoal,filtered, acidified, and extracted with ether. The ethereal solution ispercolated through a short column of alumina, which is then eluted withether. Evaporation of the solvent furnishes a-ethyla-hydroxy-4-cyclohexy1-3-fluorophenyl acetic acid. M.P. 163-165 C.

When the a-hydroxy-a-methyl-2-, 5- and 6-amino acetic acid compoundsobtained from Example 26 are used in place ofa-ethyl-a-hydroxy-3-amino-4-cyclohexylphenyl acetic acid in the aboveexample, there are obtained the corresponding u-hydroxy-a-methyl-2-, 5-and 6-fluoro acetic acid compounds.

EXAMPLE 29 a-Methylene-3-chloro-4-cyclohexylphenyl acetic acid Asolution of 5.0 grams of a-hydroxy-a-methyl- 3-chloro-4-cyclohexylphenylacetic acid and 2.0 grams of p-toluenesulfonic acid in 100 cc. tolueneis refluxed for 3 hours. The reaction mixture is cooled, 50 cc. etheradded, the resulting solution is Washed Well with water, dried oversodium sulfate, and concentrated in vacuo. The residue thus obtained iscrystallized from hexane to yield 4.1 grams ofa-methylene-3-chloro-4-cyclohexylphenyl acetic acid. M.'P. 12'913l C.

When u-hydroxy-a-methyl-3-bromo-4-cyclohexylphenyl acetic acid,a-hydroxy-a-methyl-3-chloro-4-cyclopentylphenyl acetic acid,a-hydroxy-a-methyl-li-chloro-4-secondarybutylphenyl acetic acid,u-hydroxy-a-methyl-4- cyclohexyl-2,S-dichlorophenyl acetic acid,a-hydroxy-amethyl-Z-bromo-S-chloro-4-cyclohexylphenyl acetic acid,a-hydroxy-a-methyl-5-bromo-2-chl0ro-4-cyclohexylphenyl acetic acid,u-hydroxy-a-methyl-4-cyclohexyl-5-tri.fluoromethylphenyl acetic acid,u-hydroxy-a-methyl-4-cycl0- hexyl-2,3-dichlorophenyl acetic acid,a-hydroxy-a-methyl- 4-cyclohexyl-3,5-dichlorophenyl acetic acid,ot-CthYl-ahydroxy-3-chloro-4-cyclohexylphenyl acetic acid, a-ethylozhydroxy-4-cyclohexyl-5-trifluoromethylphenyl acetic acid,a-hydroxy-a-methyl-4-cyclohexyl-3-nitrophenyl acetic acid,u-hydIOXy-u-methyl-S-chloro-4-cyclohexyl-2- nitrophenyl acetic acid,L-hYd1'OXy-tX-II1Cthy1-3-amiI10-4- cyclohexylphenyl acetic acid,a-hydroxy-a-methyl-Z- amino--chloro-4-cyclohexylphenyl acetic acid,whydroxy-rx-methyl-4-cyclohexyl-3-methylsulfonylpheny1 acetic acid,a-hydroxy-a-methyl-3-substituted-2-, 5- and 6-substituted-4-cyclohexylphenyl acetic acid compounds, thea-hydroxy-vt-methyl-2-, 5- and 6-amino acetic acid compounds obtainedfrom Example 26, the u-hydroxy-rxmethyl-2-, 5- and 6-hydroxy acetic acidcompounds obtained from Example 27 and the a-hydroxy-a-methyl-2-, 5- and6-fluoro acetic acid compounds obtained from EX- ample 28 are used inplace of a-hydroxy-a-methyl-3- chloro-4-cyclohexylphenyl acetic acid inthe above example, there are obtaineda-methyIene-S-brorno-4-cyclohexylphenyl acetic acid,a-methylene-3-chloro-4-cyclopentylphenyl acetic acid,u-methylene-3-chloro-4-secondarybutylphenyl acetic acid,u-methylene-4-cyclohexyl-2,5- dichlorophenyl acetic acid,u-methylene-Z-brOmO-S- chloro-4-cyclohexylphenyl acetic acid,a-methylene-S- bromo-2-chloro-4-cyclohexylphenyl acetic acid,a-methylene-4-cyclohexyl-S-trifluoromethylphenyl acetic acid,ocmethylene-4-cyclohexyl-2,3-dichlorophenyl acetic acid,amethylene-4-cyclohexyl-3,S-dichlorophenyl acetic acid,aethylidene-3-chloro-4-cyclohexylphenyl acetic acid (M.'P. 175-176 C.),a-ethylidene-4-cyclohexyl-5-trifiuoromethylphenyl acetic acid,a-methylene-4-cyclohexyl-3-nitrophenyl acetic acid,a-methylene-S-chloro-4-cyclohexyl-2- nitrophenyl acetic acid,a-methylene-3-amino-4-cyclohexylphenyl acetic acid, a-methylene-2amino-5-chlor0-4- cyclohexylphenyl acetic acid,a-methylene-4-cycloheXyl-3- methylsulfonylphenyl acetic acid,a-methylene-3-substituted2-, 5- and 6-substituted-4-cyclohexylphenylacetic acid compounds, a-methylene-2-, 5- and 6-amino acetic acidcompounds, a-methylene-2-, 5- and 6-hydroxy acetic acid compounds, anda-methylene-2-, 5- and 6-fluoro acetic acid compounds, respectively.

EXAMPLE 30 a-Methyl-3-chloro-4-cyclohexylphenyl acetic acid A solutionof 2.33 grams of a-methylene-3-chloro-4- cyclohexylphenyl acetic acid in25 cc. of ethanol containing 0.1 gram platinum oxide is treated withhydrogen at room temperature. After the required amount of hydrogen hasbeen taken up, the reaction mixture is filtered and concentrated to anoil which solidifies upon the addition of petroleum ether.Recrystallization from hexane gives 1.4 grams ofa-methyl-3-chloro-4-cyclohexylphenyl acetic acid. M.P. 8485.5 C.

When using a-methylene-3-bromo-4-cyclohexylphenyl acetic acid,a-methylene-3-chloro-4-cyclopentylphenyl acetic acid,a-methylene-B-chloro-4-secondarybutylphenyl acetic acid,a-methylene-4-cyclohexyl-2,S-dichlorophenyl acetic acid,u-methylene-2-bromo-5-ch-loro-4-cyclohexylphenyl acetic acid,u-methylene-S-bromo-2-chloro-4-cyclohexylphenyl acetic acid,a-methylene-4-cycloheXyl-S- 'trifluoromethylphenyl acetic acid,a-methylene-4-cycl-ohexyl-2,3-dichlorophenyl acetic acid,a-methylene-4-cyclohexyl-3,5-dichlorophenyl acetic acid,a-ethylidene-3-chloro-4- cyclohexylphenyl acetic acid,u-ethylidene-4-cyclohexyl-5- trifluoromethyl-phenyl acetic acid,zx-methylene-3-amino-4- cyclohexylphenyl acetic acid,rx-methylene-2-amino-5- chloro-4-cyclohexylphenyl acetic acid,a-methylene-4-cyclohexyl-3-methylsulfonylphenyl acetic acid, anda-methylene-3-substituted, 2-, 5- and 6-substituted-4-cyclohexylphenylacetic acid compounds, u-methylene-2-, 5- and 6- amino acetic acidcompounds, a-methylene-2-, 5- and 6- hydroxy acetic acid compounds anda-methylene-L, 5- and 6-fluoro acetic acid compounds obtained fromExample 29 in place of a-methylene-3-chl0ro-4-cyclohexylphenyl aceticacid in the above example, there are obtainedu-methyl-3-bromo-4-cyclohexylphenyl acetic acid, a-methyI-S-chloro-4-secondarybutylphenyl acetic acid, m-methyl-4-cyclohexyl-2,S-dichlorophenyl acetic acid (M.P. 1'65-167 C.a-methyl-2-bromo-5-chloro-4-cyclohexylphenyl acetic acid, u-methyl-5bromo-2-chloro-4-cyclohexylphenyl acetic acid,u-methyl-4-cyclohexyl-5-trifluoromethylphenyl acetic acid (M.P. 104-106C.), a-methyl-4-cyclohexyl- 2,3-dichlorophenyl acetic acid,u-methyl-4-cyclohexyl-3,5- dichlorophenyl acetic acid,methyl-3-chloro-4-cyclohexylphenyl acetic acid (M.P. 9798 C.),u-ethyl-4-cyclohexyl-5-trifluoromethylphenyl acetic acid,u-methyl-3-amino- 4-cyclohexylphenyl acetic acid, a-methyl-2-amino-5-chloro-4-cyclohexylphenyl acetic acid, umethyl-4-cyclohexyl-3-methylsulfonylphenyl acetic acid, a-methyl-3-substituted, 2-, 5- and 6-substituted-4-cyclohexylphenyl acetic acidcompounds, a-methyl-2-, 5- and 6-amino acetic acidcompounds,a-methyl-2-, 5- and 6-hydroxy acetic acid compounds and a-methy1-2-, 5-and 6-fluoro acetic acid compounds, respectively.

EXAMPLE 31 a-Methyl-S-chloro-4-cyclohexylphenyl acetic acid To asolution of 1.8 grams of a-hydroxy-a-methyl-3- chl0ro-4-cyclohexylphenylacetic acid in 40 ml. of glacial acetic acid is added 0.79 gram ofphosphorus and 0.32 gram of iodine. The mixture is then refluxed for 1 6hours, filtered While hot, and the filtrate poured into 150 ml. of icewater. The mixture is then filterm and the cake thus obtained dissolvedin chloroform, washed with water, dried over magnesium sulfate,charcoaled, and the solvent removed in vacuo. The residue is esterifiedby refluxing with 15 ml. of methanol and 0.15 ml. of sulfuric acid for 3hours. The solution is then diluted with ether and the reaction mixturethen washed freely of sulfuric acid (with Water), dried over magnesiumsulfate, and concentrated in vacuo. The methyl ester thus obtained ischromatographed on 75 grams of silica gel using a benzene-petroleumether system. Two compounds are obtained, which are later saponifiedseparately. The larger fraction is dissolved in 20 ml. of ethanol towhich 0.7 gram of potassium hydroxide in 3 ml. of water is added. Themixture is then refluxed for 5 hours, diluted with Water, and most ofthe methanol removed in vacuo. At this point, the solution is acidifiedwith cold 6N hydrochloric acid. The desireda-methyl-3-chloro-4cyclohexylphenyl acetic acid is obtained byfiltration from the acetic solution and recrystallization from ice-coldhexane. The second product obtained during the phosphorus iodinereduction and subsequently isolated as the methyl ester is theunsaturated analogue, a-methylene-S-chloro- 4-cyclohexy1phenyl aceticacid. M.P. 129131 C.

EXAMPLE 32 Hydrochloride of a-ethyl-4-cyclohexyl-3-dimethylaminophenylacetic acid To a solution of 1.42 grams (0.005 mole) of thehydrochloride of a-ethyl-3-amino-4-cyclohexylphenyl acetic acid in 50cc. methanol is added 0.5 gram of anhydrous sodium acetate, 4 cc. of 37%formaldehyde, and 1.5 grams of 10% palladium on charcoal. The mixture isthen hydrogenated at room temperature and 40 p.s.i. The reaction mixtureis filtered and the solids Washed with fresh methanol. The combinedmethanol filtrate is then evaporated in vacuo and the residue isextracted with boiling benzene. Evaporation in vacuo of the benzeneextract results in a residual yellow oil. This oil is dissolved inconcentrated hydrochloric acid, filtered, and diluted with water toprecipitate an oil, which soon crystallizes. The solid is filtered andwashed With cold dilute hydrochloric acid. An additional amount ofproduct is obtained from the filtrate. The product is air dried at roomtemperature and the analytical data indicates that there is solvationwith one mole of water.

When the amethyl-2-, and 6-amino acetic acid compounds obtained fromExample 30 are used in place of a-ethyl-3-amino-4-cyclohexylphenylacetic acid in the above example, there are obtained the correspondinga-methyl-2-, 5- and 6-dimethylamino acetic acid compounds.

EXAMPLE 33 a-Ethyl-3 -acetylamino-4-cyclohexylphenyl acetic acid When a:ethyl a. hydroxy 3 amino 4 cyclohexylphenyl acetic acid is treated withphosphorus and iodine in acetic acid solution, as in Example 31, theproduct is at ethylidene 3 acetylamino 4 cyclohexylphenyl acetic acid,M.P. 197199 C. The latter compound is then hydrogenated, as described inExample 30, to obtain a-ethyl-3-acetylamino-4-cyclohexylphenyl aceticacid, M.P. 181182 C.

When the a-hydroxy-a-methyl-2-, 5- and 6-amino acetic acid compoundsobtained from Example 26 are used in place ofa-ethyl-a-hydroxy-3-amino-4-cyclohexylphenyl acetic acid in the aboveexample, there are obtained the corresponding u-methyl-2-, 5- and6-acetylamino acetic acid compounds.

EXAMPLE 34 a-Ethyl-4-cyclohexyl-3-methoxyphenyl acetic acid A solutionof 0.5 gram of u-ethyl-4-cyclohexyl-3-hydroxyphenyl acetic acid in 2.5ml. of 2.5 N sodium hydroxide solution is treated with 0.6 ml. ofdimethyl sulfate and the mixture heated at 95 C. with stirring for 0.5hour, at which time 0.5 ml. of 2.5 N sodium hydroxide solution is added.Heating is continued for 0.5 hour more, at which time 3.0 ml. of 2.5 Nsodium hydroxide solution and 0.5 ml. of dimethyl sulfate are added.Heating and stirring are then continued for 16 hours. 5 ml. of 2.5 Nsodium hydroxide solution are subsequently added, and the mixture isheated at reflux for 1 hour. The mixture is cooled, acidified withhydrochloric acid. The product is extracted into ether, Washed withWater, dried with magnesium sulfate, and the solvent expelled.Trituration with hexane yields 0.37 gram ofa-ethyl-4-cyclohexyl-3-methoxyphenyl acetic acid, M.P. 134-135 C.

When the a-methyl-2-, 5- and 6-hydroxy acetic acid compounds obtainedfrom Example 30 are used in place ofa-ethyl-4-cyclohexyl-3-hydroxyphenyl acetic acid in the above example,there are obtained the corresponding a-methyl-2-, 5- and 6-methoxyacetic acid compounds.

EXAMPLE 35 a-Methyl-3-cyano-4-cyclohexylphenyl acetic acid A mixture of10 millimoles of a-methyl-3-amino-4- cyclohexylphenyl acetic acid, 3 ml.of concentrated bydrochloric acid, and grams of ice is diazotized byadding a concentrated aqueous solution of sodium nitrite until a slightexcess of nitrous acid is present. The solution is carefully neutralizedby adding solid sodium carbonate and is then added slowly to a solutionof 15 millimoles of cuprous cyanide and 30 millimoles of potassiumcyanide in 10 ml. of water kept at 5 C. The

temperature of the solution is slowly increased to 50-60 C. until thediazonium salt has decomposed. After cooling, the mixture is renderedacidic and is extracted with benzene. The benzene solution is dried andchromatographe'd on silica gel to obtaina-methyl-3-cyano-4-cyclohexylphenyl acetic acid.

When the a-methyl-2-, 5- and 6-amino acetic acid compounds obtained fromExample 30 are used in place of a-methyl-3-amino-4-cyclohexylphenylacetic acid in the above example, there are obtained the correspondingamethyl-2-, 5- and 6-cyano acetic acid compounds.

EXAMPLE 36 a-Methyl-3-carboxamido-4-cyclohexylphenyl acetic acid Twograms of a-methyl-3-cyano-4-cyclohexylpheny1 acetic acid are dissolvedin 10 ml. of concentrated sulfuric acid and kept at room temperature for24 hours. The solution is poured into 150 ml. of ice-water mixture, theprecipitated product collected and chromatographed on silica gel toobtain a-methyl-3-carboxamido-4-cyclohexylphenyl acetic acid.

When the a-methyl-2-, 5 and 6-cyano acetic acid compounds obtained fromExample 35 are used in place of a-methy1-3-cyano-4-cyclohexylphenylacetic acid in the above example, there are obtained the correspondinga-Il'lethYl-Z, 5- and 6-carboxamido acetic acid compounds.

EXAMPLE 37 Methyl a-methyl-4-cyclohexylphenyl acetate A mixture of 0.01mole of a-methyl-4-cyclohexylphenyl acetic acid and 8 ml. ofconcentrated sulfuric acid and 250 ml. of anhydrous methanol (ca. 3%sulfuric acid) is stirred at room temperature overnight. The solution isthen concentrated in vacuo to approximately 6 the volume. ml. of waterare added and the mixture extracted with (3X50 m1.) ether. The combinedether extracts are washed with saturated potassium bicarbonate solutionand water. The ether solution is then dried over magnesium sulfate,filtered, and concentrated to a residue. The residue is thenchromatographed on a silica gel column (wt/wt. 50:1 gram crude) using anether-petroleum ether sys tem (v./v. 2060%) as eluent to obtain methyla-methyl- 4-cyclohexylpheny1 acetate.

When u-ethyl-4-cyclohexylphenyl acetic acid, a-methyl-4-cyclopenty1phenyl acetic acid, and a-methyl-4-secondarybutylphenylacetic acid are used in place of a-methyl- 4-cyclohexylphenyl aceticacid in the above example, there are obtained methyla-ethyl-4-cyclohexylphenyl acetate, methyl a-methyl-4-cyclopentylphenylacetate, and methyl a-methy1-4-secondarybutylphenyl acetaterespectively.

EXAMPLE 38 Methyl a-methyl-4-cyclohexyl-3-nitrophenyl acetate To ml. ofconcentrated sulfuric acid maintained at 5 to 5 C. is added whilestirring 0.03 mole of methyl a-methyl-4-cyclohexylphenyl acetate. Thereis then added dropwise 15 cc. of fuming nitric acid, the temperaturebeing maintained at 5 to 5 C. during the addition and for 1 hourafterward. The reaction mixture is then poured onto ice and extractedwith ether. The combined ether extracts are washed well with water,dried over sodium sulfate, and concentrated to a residue. The residue isthen chromatographed on 500 grams of silica gel. Elution with 10%ether-petroleum ether yields methyl a-methyl-4-cyclohexyl-3-nitrophenylacetate.

When using methyl u-ethyl-4-cyclohexylphenyl acetate, methyla-methyl-4-cyclopentylphenyl acetate, and methyl a-methyl 4secondarybutylphenyl acetate in place of methyla-methyl-4-cyclohexylphenyl acetate in the above example, there areobtained methyl a-ethyl-4-cyclohexyl 3-nitrophenyl acetate, methyla-methyl-4-cyclopentyl-3- ondarybutylphenyl acetate respectively.

27 EXAMPLE 39 u-Methyl-4-cyclohexyl-3-nitrophenyl acetic acid To asolution of ml. of N aqueous potassium hydroxide is added a solution of0.02 mole of methyl a-methyl-4-cyclohexyl-3-nitrophenyl acetate in 45ml. of ethanol and the combined solutions stirred at room temperatureovernight. The ethanol is then removed in vacuo, 100 ml. of water added,and the mixture extracted with (2X50 ml.) ether. The aqueous layer isthen filtered, acidified with dilute aqueous hydrochloric acid, and themixture filtered. The resulting cake is washed several times with waterand dried in vacuo to yield a-methyl-4- cyclohexyl-3-nitrophenyl aceticacid.

When methyl a-ethyl4-cyclohexyl-3-nitrophenyl acetate, methylu-methyl-4-cyclopentyl-3-nitrophenyl acetate, and methyl u-methyl-3nitro 4 secondarybutylphenyl acetate are used in place of methyla-methyl-4cyclohexyl- 3-nitrophenyl acetate in the above example, thereare obtained a-ethyl-4 cyclohexyl 3 nitrophenyl acetic acid, a-methyl-4cyclopentyl 3 nitrophenyl acetic acid, anda-methyl-3-nitro-4-secondarybutylphenyl acetic acid respectively.

EXAMPLE 40 Sodium a-methyl-3-chloro-4-cyclohexylphenyl acetate Asolution of 0.01 mole of sodium hydroxide in ml. of water is added withstirring to a solution of 0.01 mole ofa-methyl-3-chloro-4-cyclohexylphenyl acetic acid in 25 ml. of methanol.At this point, additional methanol is added as needed to obtain completesolution and the solution stirred for 1 hour. The solution is thenevaporated in vacuo to obtain a residue of sodium a-methyl-3-chloro-4-cyclohexylphenyl acetate.

When potassium hydroxide is used in place of sodium hydroxide in theabove example, there is obtained the corresponding potassium salt.

When ethylamine, N,N-dimethylaminoethanol, N,N-diethylethanolamine,triethylamine, piperazine, morpholine, and choline are used in place ofsodium hydroxide in the above example and are dissolved in methanol inplace of water, there are obtained the corresponding ethylamine,N,N-dimethylaminoethanol, N,N-diethylethanolamine, triethylaminepiperazine, morpholine, and choline a-methyl-3-chloro-4-cyclohexylphenylacetic acid salts, respectively.

When a methyl 3 bromo 4 cyclohexylphenyl acetic acid, a methyl 3 chloro4 cyclopentylphenyl acetic acid, a methyl 3 chloro 4secondarybutylphenyl acetic acid, a methyl 4 cyclohexyl 2,5dichlorophenyl acetic acid, a methyl 2 bromo 5-chloro- 4cyclohexylphenyl acetic acid, a methyl 5 bromo- 2 chloro 4cyclohexylphenyl acetic acid, at methyl- 4 cyclohexyl 5trifluoromethylphenyl acetic acid, 0:- methyl 4 cyclohexyl 2,3dichlorophenyl acetic acid, a methyl 4 cyclohexyl 3,5 dichlorophenylacetic acid, at ethyl 3 chloro 4 cyclohexylphenyl acetic acid, a ethyl 4cyclohexyl 5 trifluoromethylphenyl acetic acid, a methyl 4 cyclohexyl 3nitrophenyl acetic acid, a methyl 5 chloro 4 cyclohexyl 2- nitrophenylacetic acid, a methyl 3 amino 4 cyclohexylphenyl acetic acid, a methyl 2amino 5-chloro- 4 cyclohexylphenyl acetic acid, at methyl 4 cyclohexyl 3methylsulfonylphenyl acetic acid, a methyl- 3 cyano 4 cyclohexylphenylacetic acid, a methyl-3- amnio 4 cyclohexylphenyl acetic acid, a methyl4- cyclohexyl 3-dimethylaminephenyl acetic acid, a-methyl- 4 cyclohexyl3 methoxyphenyl acetic acid, a-methyl- 3 carboxamido 4 cyclohexylphenylacetic acid, amethyl-3-acetylamino-4-cyclohexylphenyl acetic acid,amethyl 4 cyclohexyl 3 hydroxyphenyl acetic acid,amethyl-4-cyclohexyl-3-methylsulfarnylphenyl acetic acid,a-methyl-3-substituted, 2-, 5- and 6-substituted-4-cyclohexylphenylacetic acid compounds, a-methyl-2-, 5- and 6-amino acetic acidcompounds, 0L-lnthyl-2-, 5- and 6 hydroxy acetic acid compounds, anda-methyl-2-, 5-, and 6-fiuoro acetic acid compounds obtained fromExample 30 are used in place of ot-methyl-3-chloro-4-cyclohexylphenylacetic acid in the above example, there are obtained the correspondingsodium salts.

EXAMPLE 41 2-(3-chloro-4-cyclohexylphenyl)- l-propanol To a well-stirredsuspension of 0.005 mole of lithium aluminum hydride in 250 cc.anhydrous ether is added dropwise a solution of 0.01 mole of a-methyl 3chloro- 4- cyclohexylphenyl acetic acid with ice-cooling. The reactionmixture is stirred at room temperature for 1 hour, after which time 10cc. of Water is added dropwise with ice-cooling. The reaction mixture ispoured into dilute sulfuric acid and the aqueous layer is extracted wellwith (2X 25 ml.) ether. The combined ether extracts are washed withwater, dilute bicarbonate and Water, then dried over sodium sulfate, andconcentrated in vacuo. The residue is then chromatographed on a silicagel column and eluted with ether-petroleum ether (IO-400%) to give2-(3-chloro-4-cyclohexylphenyl)-1-propanol. Whena-methyl-3-bromo-4-cyclohexylphenyl acetic acid,

a-methyl-S-chloro-4-cyclophentylpbenyl acetic acid,

a-methyl-3-chloro-4-secondarybutylphenyl acetic acid,

a-methyl-4-cyclohexyl-2,S-dichlorophenyl acetic acid,

a-methyl-2-bromo-5-chloro-4-cyclohexylphenyl acetic acid,

a-methyl-5-bromo-2-chloro-4-cyclohexylphenyl acetic acid,

a-methyl4-cyclohexyl-S-trifiuoromethyl phenyl acetic acid,

a-methyl-4-cyclohexyl-2,3-dichlorophenyl acetic acid,

u-methyl-4-cyclohexyl-3,S-dichlorophenyl acetic acid,

a-ethyl-S-chloro-4-cyclohexylphenyl acetic acid,

a-ethyl-4-cyclohexyl-S-trifluoromethylphenyl acetic acid,

m-methyl-4-cyclohexyl-3-methylthiophenyl acetic acid,

a-methyl-4-cyclohexyl-3-methoxyphenyl acetic acid,

u-methyl-4-cyclohexyl-3-dimethylaminophenyl acetic acid,

and a-methyl-3-substituted, 2-, 5- and 6-substituted-4- cyclohexylphenylacetic acid,

a-methyl-2-, 5- and 6-amino acetic acid, a-methyl-2-, 5-

and 6-hydroxy acetic acid and a-methyl-2-, 5- and 6-fluoro acetic acidcompounds obtained from Example 30 (except those compounds containing anitro group) are used in place of a-methyl-3-chloro-4-cyclohexylphenylacetic acid in the above example, there are obtained 2-3-bromo-4-cyclohexylphenyl) l-propanol, 2- 3-chloro-4-cyclopentylphenyl) -1-propanol, 2-(3-chloro-4-secondarybutylphenyl)-1-propanol, 2-(4-cyclohexyl- 2,5-dichlorophenyl)-1-propa.nol,

2-(2-bromo-5-chloro-4-cyclohexylphenyl)-1-propanol,

2- 5-bromo-2-chloro-4-cyclohexylphenyl l -propanol,

2 4-cyclohexyl-S-trifluoro-methylphenyl -1-propanol,

2-(4-cyclohexyl-2,3-dichlorophenyl)-1-propanol,

2-(4-cyclohexyl-3,S-dichlorophenyl)-1-propanol,

2-( 3-c-hloro-4-cyclohexylphenyl) -1-butanol,

2- (4-cyclohexyl-5-trifiuoromethylphenyl) -1-butanol,

2- 4-cyclohexyl-3 -methylthiophenyl 1 -pro pan ol,

2- (4-cyclohexyl-3-methoxyphenyl -1-propanol,

2-(4-cyclohexyl-3-dimethylaminophenyl) -1-propanol,

and 2-(3-substituted, 2-, 5- and6-substituted-4-cyclohexylphenyl)-1-propanol, 2-(2-, 5- and6-amino)-1-propanol, 2-(2-, 5- and 6-hydroxy)-l-propanol and 2-(2-, 5-and 6-fiuoro)-l-propanol compounds, respectively.

been cooled to 0 C. is added dropwise a solution of 0.01 mole of2-(3-chloro 4 cyclohexylphenyl) 1 propanol in cc. dimethylformarnide.The reaction mixture is stirred for minutes and 0.015 mole of methyliodide is then added dropwise. The mixture is allowed to stir overnightat room temperature. 200 ml. of water is added and the resulting mixtureextracted well with ether. The combined ether extracts are washed withwater, dried over sodium sulfate, and concentrated. The residue ischromatographed on 250 grams of silica gel and eluted withether-petroleum ether 10-80%) to yield methyl-2-(3-chloro-4-cyclohexylphenyl) -l-propyl ether.

When ethyl iodide, allyl bromide, benzyl chloride, and ethoxyethylchloride are used in place of methyl iodide in the above example, thereobtained ethyl-2-(3-chloro-4-cyclohexylphenyl)-1-propyl ether,a1lyl-2-(3-chloro-4-cyclohexylphenyl)-l-propyl ether,benzyl-2-(3-chloro-4-cyclohexylphenyl)-1-propyl ether, andethoxyethyl-Z-(3-chloro-4-cyclohexylphenyl)-1- propyl etherrespectively.

When 2- (3-bromo-4-cyclohexylphenyl -1-propanol,2-(3-chloro-4-cyclopentylphenyl) -1-propanol,2-(3-chloro-4-secondarybutylphenyl)l-propanol,2-(4-cyclohexyl-2,S-dichlorophenyl)-l-propanol,2-(2-bromo-5-chloro-4-cyclohexylphenyl)-1-propanol,2-(5-bromo-2-chloro-4-cyclohexylphenyl)-1-propanol,

2- 4-cyclohexyl-5 -trifluoro-methylphenyl) l-propanol,

2-(4-cyclohexyl-2,3-dichloro-phenyl)-1-propan0l,

2-(4-cyclohexyl-3,S-dichlorophenyl)-1-propanol,

2- 3-chloro-4-cyclohexylphenyl) -l-butanol,

2-(4-cyclohexyl-S-trifluoromethylphenyl)-l-butanol,

2- (4-cyc10hexyl-3 -methylthio henyl -1-propanol,

2- (4-cyclohexyl-3 -methoxyphenyl -l-propano1,

2-(4-cyclohexyl-3-dimethylaminophenyl)-1-propanol,

2-(3-substituted-2-, 5- and 6-substituted-4-cyclohexylphenyl) 1propanol, 2-(2-, 5- and 6amino)-1-propanol,

2-(2-, 5- and 6-hydroxy)-1-propanol and 2-(2-, 5- and6-fluoro)-1-propanol compounds obtained from Example 41 are used inplace of 2-(3-chloro-4-cyclohexylphenyl)- l propanol in the aboveexample, there are obtainedmethyl-2-(3-bromo-4-cyclohexylphenyl)-1-propyl ether,

methy1-2-( 3-chloro-4-cyclopentylphenyl)-1-propyl ether,

methyl-Z- (3 -chloro-4-secondarybutylphenyl)-1-propy1 ether,

methyl-Z- 4-cyclohexyl-2,S-dichlorophenyl) -1-propyl ether,

methyl-2-(2-bromo-5-chloro-4-cyclohexylphenyl-l-propyl ether,

methyl-Z- (5 -bromo-2-chloro-4-cyclohexyl phenyl) -1-propyl ether,

methyl-2-(4-cyclohexyl-5-trifluoromethylphenyl)-1-propyl ether,

methyl-2- 4-cyclohexyl-2,3 -dichlorophenyl) -1-propyl ether,

methyl-2-(4-cyclohexyl-3,S-dichlorophenyl)-1-propyl ether,

methyl-Z-(3-chloro-4-cyclohexylphenyl)-1-butyl ether,

methyl-Z- (4-cyclohexyl-S-trifluoromethylphenyl) -1-butyl ether,

methyl-2-(4-cyclohexyl-3-methylthiophenyl)-l-propyl ether,

methyl-2-(4-cyclohexyl-3-methoxyphenyl)-l-propyl ether,

methyl-Z- (4-cyclohexyl-3-dimethylaminophenyl) -1-propyl ether,

methyl-2-(3-substituted, 2-, 5 and 6-substituted-4-cyclohexylphenyl)-1-propyl ether,

methy1-2-(2-, 5- and 6-amino)-1-propyl ether,

methyl-2-(2-, 5- and 6- hydroxy)-1-propyl ether and methyl-2-(2-, 5- and6-flu0ro)-1-propyl ether, respectively.

EXAMPLE 43 a-Methyl-3-chloro-4-cyclohexyphenyl acetaldehyde (A)m-methyl-3-chloro-4-cyclohexylphenyl acetyl chloride-To a solution of0.01 mole of T-methyl-3-chloro- 4-cyclohexylphenyl acetic acid in 50 cc.of benzene is added 0.011 mole of thionyl chloride. The solution isheated on the steam bath for 1 hour and then concentrated in vacuo toremove the solvent and any excess thionyl chloride. 25 ml. of benzene isthen added and removed in vacuo to yielda-methyl-3-chloro-4-cyclohexylphenyl acetyl chloride.

(B) a-methyl-3-chloro-4-cyclohexylphenyl acetaldehyde-To a suspension of0.01 mole tritertiarybutoxy lithium aluminum hydride in 50 cc. drytetrahydrofuran is added dropwise with stirring a solution of 0.01 moleof a-methyl-3-chloro-4-cyclohexylphenyl acetyl chloride in 25 cc. drytetrahydrofuran. The reaction mixture is stirred at -10 C. for 3 hoursfollowed by the addition of 200 cc. of 5% sulfuric acid addedcautiously, and the resultant mixture extracted well with (3X 75 ml.)ether. The combined ether extracts are washed with water, dried oversodium sulfate, and concentrated. The residue is chromatographed on 250grams of silica gel and eluted with 10-90% ether-petroleum ether toyield a-methyI-B-chloro-4-cyclohexylphenyl acetaldehyde.

When ot-methyl-3-bromo-4-cyc1ohexylphenyl acetic acid,a-methyl-3-chloro-4-cyclopentylphenyl acetic acid,a-methyl-3-chloro-4-secondarybutylphenyl acetic acid,ot-methyl-4-cyclohexyl-2,S-dichlorophenyl acetic acid,u-methyl-Z-bromo-5-chloro-4-cyclohexylpheny1 acetic acid,amethyl-5-bromo-2-chloro-4-cyclohexylphenyl acetic acid,a-methyl-4-cyclohexyl-5-trifiuoromethylphenyl acetic acid,a-methyl-4-cyclohexyl-2,3-dichlorophenyl acetic acid,m-methyl-4-cyclohexyl3,5-dichlorophenyl acetic acid,a-ethyl-3-chloro-4-cyclohexylphenyl acetic acid,ot-ethyl-4-cyclohexyl-5-trifiuoromethylphenyl acetic acid,a-methyl-4-cyclohexyl-3-nitrophenyl acetic acid,a-methyl-5-chloro-4-cyclohexyl-Z-nitrophenyl acetic acid,a-methyI-Z-amino-5-chloro-4-cyclohexylphenyl acetic acid,u-methyl-4-cyclohexyl-3-methylsulfonylphenyl acetic acid, andot-methyl-3-substituted, 2-, 5- and 6-substituted-4-cyclohexylphenylacetic acid compounds, a-methyl-2-, 5- and 6-amino acetic acidcompounds, a-methyl-2-, 5- and 6-hydroxy acetic acid compounds anda-methyl-2-, 5- and 6-fluoro acetic acid compounds obtained from Example30 (except those compounds containing a nitro group) are used in placeof a-methyl-3- chloro-4-cyclohexylphenyl acetic acid in Part A of theabove example and the product thereof used in Part B of the aboveexample, there are obtained oc-methyl-3-bromo-4-cyclohexylphenylacetaldehyde, a-methyl-3-chloro-4-cyclopentylphenyl acetaldehyde,u-methyl-3-chloro-4-secondary-butylphenyl acetaldehyde,a-methyl-4-cyclohexyl-2,S-dichlorophenyl acetaldehyde,a-r1r11ethyl-2-bromo-5-chloro-4-cyclohexylphenyl acetaldeyot-methyl-5-bromo-2-chloro-4-cyclohexylphenyl acetaldehyde,a-methyl-4-cyclohexyl-S-trifluoromethylphenyl acetaldehyde,m-methyl-4-cyclohexyl-2,3-dichlorophenyl acetaldehyde,ot-methyl-4-cyclohexyl-3,S-dichlorophenyl acetaldehyde,u-ethy1-3-chloro-4-cyclohexylphenyl acetaldehyde,ot-ethyl-4-cyclohexyl-S-trifluoromethylphenyl acetaldehyde,ot-methyl-4-cyclohexyl-3-nitrophenyl acetaldehyde,oc-methyl-5-chloro-4-cyclohexyl-Z-nitrophenyl acetaldehyde,a-methyI-Z-amino-5-chloro-4-cyclohexylphenyl acetaldehyde,ot-methyl-4-cycloheXyl-3-methylsulfonylphenyl acetaldehyde, andu-methyI-S-Substituted, 2-, 5- and 6-substituted-4-cyclohexylphenylacetaldehyde compounds, a-rnethyl-2-, 5- and 6-amino acetaldehydecompounds, a-methyl-2-, 5- and 6-hydroxy acetaldehyde compounds and 31m-methyl-L, and 6-fluoro acetaldehyde compounds (except those compoundscontaining a nitro group) respectively.

EXAMPLE 44 u-Methyl-3-chloro-4-cyclohexylphenyl acetaldehyde dimethylacetal To a solution of 0.01 mole ofu-methyl-3-chloro-4-cyclohexylphenyl acetaldehyde in 100 cc. ofanhydrous methanol is added 0.001 mole of p-toluenesulfonic acid. Thereaction mixture is stirred at room temperature for 5 days. A solutionof sodium methoxide in methanol is added until the solution is justalkaline to moistened litmus paper. The methanol is removed in vacuo andthe residue taken up in ether and washed well with water. The ethersolution is dried over sodium sulfate and concentrated. The residue ischromatographed on neutral alumina. Elution with ether-petroleum ether(90%) gives the dimethyl acetal of u-methyl-3-chloro-4-cyclohexylphenylacetaldehyde.

When ethanol, n-propanol, and n-butanol are used in place of methanol inthe above example, there are obtained the corresponding diethyl,dipropyl, and dibutyl acetals.

When

a-methyl-B-bromo-4-cyclohexylphenyl acetaldehyde,a-methyl-3-chloro-4-cyclopentylphenyl acetaldehyde,a-methyl3-chl0ro-4-secondarybutylphenyl acetaldehyde,a-methyl-4-cycl0hexyl-2,S-dichlorophenyl acetaldehyde,u-methyl-2-bromo-5-chloro-4-cyclohexylphenyl acetaldehyde,a-methyl-5-bromo-2chloro-4-cyclohexylphenyl acetaldehyde,a-methyl-4-cyclohexyl-S-trifluorornethylphenyla-methyl-4-cyclohexyl-2,3-dichlorophenyl acetaldehyde,a-methyl-4-cyclohexyl-3,5-dichlorophenyl acetaldehyde,a-ethyl-3-chloro-4-cyclohexylphenyl acetaldehyde,a-ethyl-4-cyclohexyl-5-trifluoromethylphenyl acetaldehyde,a-methyl-4-cyclohexyl-3-nitrophenyl acetaldehyde,u-methyI-S-chloro-4-cyclohexyl-2-nitrophenyl acetaldehyde,a-methyl-Z-amino-5-chloro-4-cyclohexylphenyla-methyl-4'cyc1ohexyl-3-methylsulfonylphenyl acetaldehyde, anda-methyl-3-substituted, 2, 5- and 6-substituted-4-cyclohexylphenylacetaldehyde, a-methyl-2-, 5- and 6-amino acetaldehyde, a-methyl-2-, 5-and 6-hydroxy acetaldehyde and a-methyl-2-, 5- and 6-fluoro acetaldehydecompounds obtained from Example 43 are used in place ofu-methyl-3-chloro-4cyclohexylphenyl acetaldehyde in the above example,there are obtained a-methyl-3-bromo-4-cyclohexylphenyl acetaldehydedimethyl acetal, a-methyl-3-chloro-4-cyclopentylphenyl acetaldehydedimethyl acetal, u-methyl-3-chloro-4-secondarybutylphenyl acetaldehydedimethyl acetal, a-methyl-4-cyclohexyl-2,S-dichlorophenyl acetaldehydedimethyl acetal, a-methyl-2-bromo-5-chloro-4-cyclohexylphenylacetaldehyde dimethyl acetal,a-methyl-S-bromo-2-chloro-4-cyclohexylphenyl acetaldehyde diemthylacetal, a-methyl-4-cyclohexyl-5-trifluoromethylphenyl acetaldehydedimethyl acetal, u-methyl-4-cyclohexyl-2,3-dichlorophenyl acetaldehydedimethyl acetal, a-methyl-4-cyclohexyl-3,S-dichlorophenyl acetaldehydedimethyl acetal, methyl-3-chloro-4-cyclohexylphenyl acetaldehydedimethyl acetal,

a-ethyl-4-cyclohexyl-5trifluoromethylphenyl acetaldehyde dimethylacetal,

a-methyl-4-cyclohexyl-3-nitrophenyl acetaldehyde dimethy acetal,

a-methyl-5-chloro-4-cyclohexyl-Z-nitrophenyl acetaldehyde dimethylacetal,

a-methyl-Z-amino-chloro-cyclohexylphenyl,

acetaldehyde dimethyl acetal,

a-methyl-4-cyclohexyl-3-methylsulfonylphenol acetaldehyde dimethylacetal,

u-methyl-3-substituted, 2-, 5- and 6-substituted-4-cyclohexylphenylacetaldehyde dimethyl acetal,

a-methyl-2-, 5- and 6-amino acetaldehyde dimethyl acetal,

u-methyl-2-, 5- and 6-hydroxy acetaldehyde dimethyl acetal anda-methyl-2-, 5- and 6-fluoro acetaldehyde dimethyl acetal compounds,

respectively.

EXAMPLE 45 a-Methyl-3-chloro-4-cyclohexylphenyl acetamide 0.05 mole ofa-methyl-3-chloro-4-cyc1ohexylphenyl acetic acid is slowly treated with0.2 mole of thionyl chloride. The resultant mixture is heated gently ona steam bath for 2 hours and the excess thionyl chloride is removed invacuo. To this concentrated material is added 40 ml. of1,2-dimethoxyethane and the solution is then added dropwise to ml. ofstirred commercial ammonium hydroxide solution (approximately 30%) withice-cooling. The a-methyl-3-chloro-4-cyclohexylphenyl acetamide iscollected, washed with water, and dried in vacuo.

When methylamine, ethanolamine, propylamine, 2,3- dihydroxybutylamine,benzylamine, aniline, o-methoxy aniline, p-ethoxy aniline,m-trifluoromethyl aniline, cyclohexylamine, car bobenzyloxymethylamine,carboxymethylamine, glutamine, aminomethyl pyrrolidine,3-aminomethyl-l-ethyl pyrrolidine, morpholine, piperazine, piperidine,and pyrrolidine are used in the above example in place of ammoniumhydroxide, there are obtained the correspondingu-methyl-3-chloro-4-cyclohexylphenyl-substituted amides.

When

a-methyl-3-bromo-4-cyclohexylphenyl acetic acid,u-methyl-3-chloro-4-cyclopentylphenyl acetic acid,a-methyl-3-chloro-4-secondarybutylphenyl acetic acid,a-methyl-4-cyclohexyl-2,S-dichlorophenyl acetic acid,a-methyl-Z-bromo-5-chloro-4-cyclohexylphenyl acetic acid,a-methy1-5bromo-Z-chloro-4-cyclohexylphenyl acetic acid,a-methyl-4-cyclohexyl-5-trifiuoromethylphenyl acetic acid,a-methyl-4-cyclohexyl-2,3-dichlorophenyl acetic acid,a-methyl4-cyclohexyl-3,5-dichlorophenyl acetic acid,a-ethyl-3chloro-4-cyclohexylphenyl acetic acid,a-ethyl-4-cyclohexyl-S-trifiuoromethylphenyl acetic acid,a-methyl-4-cyclohexyl3-nitrophenyl acetic acid,a-methyl-S-chloro-4-cyclohexyl-2-nitrophenyl acetic acid,a-methyl-3-arnino-4-cyclohexylphenyl acetic acid,a-methyl-2-amino-5-chloro-4-cyclohexylphenyl acetic acid,a-methyl-4-cyclohexyl-3-methylthiophenyl acetic acid,a-methyl-4-cyclohexyl-3-methoxyphenyl acetic acid,

a-methyl-3-substituted, 2-, 5- and 6-substituted-4-cyclohexylphenylacetic acid compounds, u-methyl-2-, 5- and 6- amino acetic acidcompounds, u-methyl-2-, 5- and 6- hydroxy acetic acid compounds anda-methyl-2-, 5- and 6- fluoro acetic acid compounds obtained fromExample 30 are used in place of a-methyl-3-chloro-4-cyclohexylphenylacetic acid in the above example, there are obtaineda-methyl-S-bromo-4-cyclohexylphenyl acetamide,a-methyl-3-chloro-4-cyclopentylphenyl acetamide,

a-methyl-3-substituted, 2-, and 6-substituted-4-cyclohexylphenylacetamide, a-methyl-2-, 5- and 6-amino acetamide, a-methyl-2-, 5- and6-hydroxy acetamide and amethyl-2-, 5- and 6-fluoro acetamide compounds,respectively (when the compound has a hydroxy group first forming thebenzylated hydroxy, and subsequent reduction back to the hydroxy).

EXAMPLE 46 a-Methy13-chloro-4-cyclohexylphenyl acetamide To a solutionof 0.01 mole of a-methy1-3-chloro-4- cyclohexylphenyl acetic acid in 40ml. of 1,2-dimethoxy ethane is added 0.01 mole of triethylamine. Theresulting mixture is ice-cooled, stirred, and 0.01 mole of i-butylchloroformate is added. Stirring is then continued in the cold for anadditional 30 minutes. The triethylamine hydrochloride is then removedby filtration and the filtrate cooled again. Dry dimethoxyethanesaturated With dry ammonia gas is then added and the ammonia gas bubbledthrough the resultant mixture for approximately one minute. The mixtureis then stirred at about 5 C. for 16 hours. The solvent is removed invacuo and the residue is crystallized from ethanol-water to yielda-IIIBthYl-3- chloro-4-cyclohexylphenyl acetamide.

When methylamine, ethanolamine, propylamine, 2,3- dihydroxybutylamine,benzylamine, aniline, o-methoxy aniline, p-ethoxy aniline,m-trifluoromethyl aniline, cyclohexylamine, carbobenzyloxymethylamine,carboxymethylamine, glutamine, aminomethyl pyrrolidine,3-aminomethyl-l-ethyl pyrrolidine, morpholine, piperazine, piperidineand pyrrolidine are used in the above example in place of ammonia gas,there are obtained the corresponding a methyl 3 chloro 4cyclohexylphenyl substituted amides.

When

a-methy1-3-bromo-4-cyclohexylphenyl acetic acid,a-methyl-3-chloro-4-cyclopentylphenyl acetic acid,u-methyl-3-chloro-4-secondarybutylphenyl acetic acid,a-methyl-4-cyclohexyl-2,S-dichlorophenylacetic acid,a-methyl-2-bromo-5-chloro-4-cyclohexylphenyl acetic acid,ot-methyl-5-bromo-2-chloro-4-cyclohexylphenyl acetic acid,a-methyl-4-cyclohexyl-S-trifiuoromethylphenyl acetic acid,u-methyl-4-cyclohexy1-2,3-dichloropheny1 acetic acid,a-methy1-4-cyclohexyl-3,S-dichlorophenyl acetic acid,a-ethyl-3-chloro-4-cyclohexylphenyl acetic acid,a-ethyl-4-cyc1ohexyl-5-trifiuoromethylphenyl acetic acid,a-methyl-4-cyclohexyl-3-nitrophenyl acetic acid,a-methyl-5-chloro-4-cyclohexyl-Z-nitrophenyl acetic acid,a-rnethyl-3-amino-4-cyclohexylphenyl acetic acid,a-methyI-Z-amino-S-chloro-4-cyclohexylphenyl acetic acid,u-methyl-4-cyclohexyl-3-methylthiophenyl acetic acid,a-methyl-4-cyclohexyl-3-methoxyphenyl acetic acid,a-methyl-4-cyclohexyl-3-methylsulfonylphenyl acetic acid,a-methyl-4-cyclohexyl-3-dimethylsulfamylphenyl acetic acid,

a-methyl-3-cyano-4-cyclohexylphenyl acetic acid, anda-methyl-3-acetylamino-4-cyclohexylphenyl acetic acid are used in placeof a-methyl-3-chloro-4-cyclohexylphenyl acetic acid in the aboveexample, there are obtained a-methyl-3-bromo-4-cyclohexylphenylacetamide, a-methyl-3-chloro-4-cyclopentylphenyl acetamide,a-methyl-3-chloro-4-secondarybutylphenyl acetamide,a-methyl-4-cyclohexyl-Z,S-dichlorophenyl acetamide,u-methyl-2-bromo-S-chloro-4-cyclohexylphenyl acetamide,a-methyl-5-bromo-2-chloro-4-cyc1ohexylphenyl acetamide,a-methyl-4-cyclohexyl-S-trifluoromethylphenyl acetamide,a-methyl-4-cyclohexyl-2,3-dichlorophenyl acetamide,u-methyl-4-cyclohexyl-3,S-dichlorophenyl acetamide,a-ethyl-3-chloro-4-cyclohexylphenyl acetamide,a-ethyl-4-cyclohexyl-5-trifluoromethylphenyl acetamide,a-methyl-4-cyclohexyl-3-nitrophenyl acetamide,a-methyI-S-chloro-4-cyclohexyl-2-nitrophenyl acetamide,a-methy1-3-amino-4-cyclohexylphenyl acetamide,a-methyl-2-amino-5-chloro-4-cyclohexylphenyl acetamide,u-methyl-4-cyclohexy1-3-methylthiophenyl acetamide,a-methyl-4-cyclohexyl-3-methoxyphenyl acetamide,a-methyl-4-cyclohexyl-3-methylsulfonylphenyl acetamide,a-methyl-4-cyclohexyl-3-dimethy1sulfamylphenyl acetamide,a-methyl-3-cy-ano-4-cyclohexylphenyl acetamide, anda-methyl-3-acetylamino-4-cyclohexylphenyl acetamide' respectively.

EXAMPLE 47 Methyl a-methyl-3-chloro-4-cyclohexylphenyl acetate A mixtureof 0.05 mole of ot-methyl-3-chloro-4-cyclohexylphenyl acetic acid, 6 ml.of concentrated sulfuric acid, and 200 ml, of anhydrous methanol (ca. 3%sulfuric acid) is stirred at room temperature overnight. The solution isthen concentrated in vacuo to approximately /3 the volume. 200 ml. ofwater are added and the mixture extracted with (3X 75 m1.) ether. Thecombined ether extracts are then washed with saturated potassiumbicarbonate solution and water. The ether solution is then dried overmagnesium sulfate, filtered, and concentrated to a residue. The residueis then chromatographed in a silica gel column (wt/Wt. 50:1 gram crude)using an ether-petroleum ether system (v./v. 2060%) as eluent to yieldmethyl a-methyl-3-chloro-4-cyclohexy1- phenyl acetate When a solution ofgaseous hydrochloric acid in methanol is used in place of the sulfuricacid-methanol solution in the above example, there is obtained methyla-methyl-3-chloro-4-cyclohexylphenyl acetate.

When ethanol, n-propanol, and i-butanol are used in place of methanol inthe above example, there are obtained the corresponding ethyl, n-propyl,and i-butyl esters of u-methyl-3-chloro-4-cyclohexylphenyl acetic acid.

When a-methyl-3-bromo-4-cyclohexylphenyl acetic acid,u-methyl-3-chloro-4-cyclopentylphenyl acetic acid,u-methyl-3-chloro-4-secondarybutylphenyl acetic acid,a-methyl-4-cyclohexyl-2,S-dichlorophenyl acetic acid,a-methyl-Z-bromo-5-chloro-4-cyclohexylphenyl acetic acid,a-methyl-5-bromo-2-chloro-4-cyclohexy1phenyl acetic acid,ot-methyl-4-cyclohexyl-S-trifluoromethylphenyl acetic acid,a-methyl-4-cyclohexyl-2,3-dichlorophenyl acetic acid,oc-methyl-4-cyclohexyl-3,S-dichlorophenyl acetic acid,u-ethyl-3-chloro-4-cyclohexylphenyl acetic acid,a-ethyl-4-cyclohexyl-5-trifluoromethylpheny1 acetic acid,a-methy1-4-cyclohexyl-3-nitrophenyl acetic acid,a-methyl-5-chloro-4-cyclohexyl-Z-nitrophenyl acetic acid,a-methyl-3-amino-4-cyclohexy1phenyl acetic acid,ot-methyl-2-amino-5-ch1oro-4-cyclohexylphenyl acetic acid,

35 a-methyl-4-cyclohexyl-3-methoxyphenyl acetic acid,a-methyl-4-cyclohexyl-3-hydroxyphenyl acetic acid,u-methyl4-cyclohexyl-3-nitrophenyl acetic acid,

and a-methyl-S-substituted, 2-, and 6-substituted-4- cyclohexylphenylacetic acid compounds, a-methyl-2-, 5- and 6-amino acetic acidcompounds, u-methyl-2-, 5- and 6-hydroxy acetic acid compounds anda-methyl-2-, 5- and 6-fiuoro acetic acid compounds obtained from Example30 are used in place of a-methyl-3-chloro-4-cyclohexylphenyl acetic acidin the above example, there are obtained methyla-methyl-3-bromo-4-cyclohexylphenyl acetate, methyla-methyl-3-chloro-4-cyclopentylphenyl acetate,

methyl a-methyl-3-chloro-4-scondarybutylphenyl acetate,

methyl a-methyl-4-cyclohexyl-2,5-dichlorophenyl acetate,

methyl a-methyl-2-bromo-5-chloro-4-cyclohexylphenyl acetate,

methyl u-methyl-5-bromo-2-chloro-4-cyclohexylphenyl acetate,

methyl u-methyl-4-cyclohexyl-S-trifluoromethylphenyl acetate,

methyl a-methyl-4-cyclohexyl-2,3-dichlorophenyl acetate,

methyl a-methyl-4-cyclohexyl-3,S-dichlorophenyl acetate,

methyl a-ethyl-3-chloro-4-cyclohexylphenyl acetate,

methyl a-ethyl-4-cyclohexyl-5-trifiuoromethylphenyl acetate,

methyl a-methyl-4-cyclohexyl-3-nitrophenyl acetate,

methyl a-methyl-4-cyclohexyl-3-nitropheny1 acetate,

methyl u-methyl-S-chloro-4-cyclohexyl-2-nitrophenyl acetate,

methyl 'a-methyl-3-amino-4-cyclohexylphenyl acetate,

methyl wmethyl-Z-amino-5-chloro-4-cyclohexylphenyl acetate,

methyl a-methyl-4-cyclohexyl-3-methoxypheny1 acetate,

methyl a-methyl-4-cyclohexyl-3-hydroxyphenyl acetate,

methyl ot-methyl-4-cyclohexyl-3-nitrophenyl acetate,

methyl-a-methyl-il-substituted, 2-, 5- and 6- substituted-4-cyclohexylphenyl acetate compounds, methyl-a-methyl- 2-, 5- andG-amino acetate compounds, methyl-a-methyl- 2-, 5- and 6-hydroxy acetatecompounds and methyl-umethyl-2-, 5- and 6-fluoro acetate compoundsrespectively.

EXAMPLE 48 t-Butyl wmethyI-S-chloro-4-cyclohexylphenyl acetate 0.05 moleof a methyl 3 -chloro-4-cyclohexylphenyl acetic acid is treated with 0.2mole of thionyl chloride and the resultant mixture gently heated on asteam bath for 2 hours. The excess thionyl chloride is then removed invacuo. 50 ml. of benzene is added and the solvent again removed invacuo. 50 ml. of fresh dry 1,2-dimethoxyethane is then added and theresultant solution slowly added to a mixture of 0.06 mole of Potassiumtertiary butoxide in 100 ml. dimethoxyethane with icecooling. Theresultant mixture is then stirred at room temperature for 4 hours andthen concentrated to a residue in vacuo, The residue is then dissolvedin ether, washed with sodium bicarbonate, dried, evaporated, andchromatographed on a silica gel column (wt/wt. 50:1 gram crude) using anether-petroleum ether (v./v. 20- 60%) system as eluent to yield t-butyla-methyl-3-chloro- 4-cyclohexylphenyl acetate.

When the sodium or potassium alkoxides of ethanol, n-propanol,i-butanol, benzyl alcohol, phenol, and phenylethanol are used in placeof potassium tertiary butoxide in the above example, there are obtainedthe corresponding ethyl, n-propyl, i-butyl, benzyl, phenyl, andphenylethyl esters of on methyl 3 chloro-4-cyclohexylpheny1 acetic acidrespectively.

When w'n'lflthyl 3-bromo 4-cyclohexylphenyl acetic acid, oz-methyl3-chloro- 4-cyclopentylphenyl acetic acid, a-methyl 3-chloro4-secondarybutylphenyl acetic acid, a-methyl 4-cyclohexyl2,5-dichlorophenyl acetic acid,

acetic acid in the above example, there are obtained methyl tx-methyl3-bromo 4-cyclohexylphenyl acetate, methyl 0: methyl3-chloro-4-cyclopentylphenyl acetate, methyl 0c methyl 3-chloro 4secondarybutylphenyl acetate, methyl a-methyl4-cyclohexyl-2,S-dichlorophenyl acetate, methyl 0; methyl2-bromo-5-chloro-4-cyclohexylphenyl acetate, methylot-methyl-5-bromo-2Fchlor0-4-cylohexylphenyl acetate, methylu-methyl-4-cyclohexyl-5-trifluoromethylphenyl acetate, methyl a-methyl4-cyclohexyl-2,3- dichlorophenyl acetate, methyl a-methyl-4cyclohexyl-3, S-dichlorophenyl acetate, methyl a-ethyl 3 chloro-4-cyclohexylphenyl acetate, methyl a-ethyl-4-cyclohexyl-5-trifluoromethylphenyl acetate, methyla-methyl-4-cyclohexyl-3-nitrophenyl acetate, methyl a-methyl-5-chloro-4-cyclohexyl-Z-nitrophenyl acetate, methyl a-methyl 3- amino-4cyclohexylphenyl acetate, methyl a-methyl 2- amino 5chloro-4-cyclohexylphenyl acetate, methyl amethyl-4-cyclohexyl 3methoxyphenyl acetate, and methyl a-methyl 4-cyclohexy1-3-nitrophenylacetate respectively.

EXAMPLE 49 Methyl a-methyl-3-chloro-4-cyclohexylphenyl acetate To asolution of 0.01 mole of m-methyl-3-chloro-4- cyclohexylphenyl aceticacid in 30 ml. of anhydrous tetrahydrofuran is added 0.011 mole ofmethanol followed by 0.001 mole of N,N-dicyclohexylcarbodiimide (whichhas been dissolved in a minimum amount of tetrahydrofuran). The mixtureis then shaken thoroughly for a minute and allowed to sit overnightstoppered. The mixture is then filtered, the precipitatedN,N-dicyclohexylurea obtained is washed with a small portion of freshtetrahydrofuran, and the wash combined with the filtrate. The combinedfiltrates are concentrated to dryness. The residue is then taken up inml. of ether, washed with bicarbonate solution, water, dried overmagnesium sulfate, filtered, and concentrated to a residue. The residueis then chromatographed on a silica gel column (wt/Wt. 50:1 gram crude)using an ether-petroleum ether (v./v. 20-60%) system as eluent to yielda-methyl-3-chloro-4 cyclohexylphenyl acetate.

When ethanol, n-propanol, i-butanol, benzyl alcohol, phenylethanol, N,Ndiethylethanolamine, and N,N-dimethylethanolamine are used in place ofmethanol in the above example, there are obtained the ethyl, n-propyl,ibutyl, benzyl, phenylethyl, N,N-diethylaminoethyl, and N,N-dimethylaminoethyl esters of a-methyl 3-chloro-4- cyclohexylphenylacetic acid respectively. The esters from the N-substitutedethanolamines are extracted from the ether olution indicated in theabove example using dilute hydrochloric acid, the acid solution washedwell with ether, made slightly alkaline with ammonium hydroxide,extracted with ether, the combined ether extracts washed with water,dried over potassium carbonate and charcoal, filtered, and the resultingether solution concentrated to a residue.

When

u-methyl-3-'bromo-4-cyclohexylphenyl acetic acid,u-methyl-3-chloro-4-cyclopentylphenyl acetic acid,a-methyl-3-chloro-4-secondarybutylphenyl acetic acid,a-methyl-4-cyclohexyl-2,S-dichlorophenyl acetic acid,

a-methyl-4-cyclohexyl-3-methoxyphenyl acetic acid,

ot-methyl-4-cyclohexyl-3-nitrophenyl acetic acid,

u-methyl-3-cyano-4-cyclohexylphenyl acetic acid,

u-methyl-3-acetylamino-4-cyclohexylphenyl acetic acid,

m-methyl-4-cyclohexyl-3-dimethylaminophenyl acetic acid,

a-methyl-4-cycloheXyl-3-methylsulfonylphenyl acetic acid,

and a-methyl 4 cyclohexyl-3-dimethylsulfamylphenyl acetic acid are usedin place of a-methyl-3-chloro-4-cyclohexylphenylacetic acid in the aboveexample, there are obtained methyl a-methyl-3-bromo-4-cyclohexylphenylacetate,

methyl a-methyl-3-chloro-4-cyclopentylphenyl acetate,

methyl a-methyl-3-chloro-4-secondarybutylphenyl acetate,

methyl a-methyl-4-cycloheXyl-2,S-dichlorophenyl acetate,

methyl a-methyl-2-bromo-5-chloro-4-cyclohexylphenyl acetate,

methyl u-methyI-S-bromo-2-chloro-4-cyclohexylphenyl acetate,

methyl a-methyl-4-cyclohexyl-S-trifluoromethylphenyl acetate,

methyl u-methyl-4-cyclohexyl-2,3-dichlorophenyl acetate,

methyl a-methyl-4-cyclohexyl-3,S-dichlorophenyl acetate,

methyl a-ethyl-3-chloro-4-cyclohexylphenyl acetate,

methyl a-ethyl-4-cyclohexyl-S-trifiuoromethylphenyl acetate,

methyl u-methyl-4-cyclohexyl-3-nitrophenyl acetate,

methyl a-methyl-5-chloro-4-cyclohexyl-2-nitrophenyl acetate,

methyl a-methyl-3-amino-4-cyclohexylphenyl acetate,

methyl a-methyI-Z-amino-5-chloro-4-cyclohexylpheny1 acetate,

methyl a-methyl-4-cyclohexyl-3-methoxyphenyl acetate,

methyl a-methyl-4-cyclohexyl-3-nitrophenyl acetate,

methyl a-methyl-3-cyano-4-cyclohexylphenyl acetate,

methyl a-methyl-3-acetylamino-4-cyclohexylphenyl acetate,

methyl u-methyl-4-cyclohexyl-3-dimethylaminophenyl acetate,

methyl a-methyl-4-cyclohexyl-3-methylsulfonylphenyl acetate, and methyla-methyl-4 cyclohexyl 3-dimethylsulfamytlphenyl acetate respectively.

EXAMPLE 50 d a-Methyl-3-chloro-4-cyclohexylphenyl acetic acid To asolution of 12.67 grams (0.042 mole) of cinchonidine in hot chloroformis added a solution of 20.9 grams of a-methyl3-chloro-4-cyclohexylphenyl acetic acid (0.0783 mole) (55% of base) in100 cc. chloroform. An exothermic reaction takes place. After 30minutes, the solution is concentrated in vacuo to remove all chloroform.The resulting oil crystallizes upon the gradual addition of acetone. Thesalt is then resolved by dissolving it in boiling acetone, distillingthe solvent at atmospheric pressure until crystals begin to appear. Thesolution is-allowed to cool to room temperature and the solid materialfiltered. This procedure is repeated until the melting point of the saltis constant at 177.7178.2 C. The [0:1 of the salt is -55.5 *-0.5. Theacid is then recovered by extracting the salt between petroleum etherand 10% hydrochloric acid. Concentration of the petroleum ether layergives an oil which gradually crystallizes. The acid thus obtained has a[M of +36.5, M.P. 61.562.0 C.

We claim:

1. A racemic compound of the formula (Rink-2 wherein:

R is chloro, bromo, fluoro, loweralkoxy, trifluoromethyl, methyl thio,mercapto, amino di(lower alkyl) amino, cyano, nitro, carboxamido, loweralkanoylamino, lower alkylsulfonyl, di(lower alkyl)sulfamoyl or hydroxy;but with the proviso that R is 2 only when R is chloro, bromo or fluoroand if R is trifluoromethyl said trifiuoromethyl group is in the 3position of the benzene moiety;

X is COOH or COOR wherein R is lower alkyl, phenyl, benzyl, phenethyl ordi(lower alkyl)amino lower alkyl;

R is hydrogen;

R is lower alkyl and when taken together R,, and R,,

are methylene or ethylidene;

and the pharmaceutically acceptable non-toxic salts of the acids.

2. The (d) form of a compound of claim 1 wherein R is as defined inclaim 1, R is hydrogen and R, is lower alkyl.

3. A racemic compound of the formula wherein:

Z is hydrogen;

R is methyl, or when taken together with Z, methylene;

R i chloro, bromo, fluoro, loweralkoxy, trifluoromethyl, methyl thio,mercapto, amino, di(lower alkyl)amino, cyano, nitro, carboxamido, loweralkanoylamino, lower alkylsulfonyl, di(lower alkyl) sulfamoyl orhydroxy; but with the proviso that R is 2 only when R is chloro, bromoor fluoro and if R is trifluoromethyl said trifluoromethyl group is inthe 3 position of the benzene moiety;

and the pharmaceutically acceptable non-toxic salts thereof.

4. The (d) form of a compound of claim 3 wherein:

R is as defined in claim 3;

R is methyl; and

Z i hydrogen.

5. dl a-Methyl-3-chloro-4-cyclohexy1phenyl acetic acid.

6. dl a Methylene-3-chloro-4-cyclohexylphenyl acetic acid.

7. dl a-Ethyl-3-chloro-4-cyclohexylphenyl acetic acid.

8. Dimethylaminoethanol salt of dl a-methyl-3-chloro- 4-cyclohexylphenylacetic acid.

9. dl Diethylaminoethyl a methyl 3 chloro-4-cyclohexylphenyl acetatehydrochloride.

10. dl a-Methyl-4-cyclohexyl-2,S-dichlorophenyl acetic acid.

39 9 '40 1 11. d1 or. Methylene 4 cyclohexyl-3-trifluoromethyl- LORRAINEA. WEINBERGER, Primary Examiner. phenyl acetic acid. 12. d-a-rnethyl(3-chloro 4-cyclohexylpheny1) acetic EDWARD GLEIMAN Assistant Exammel'acld- R f Ct d US. 01. X.R.

e e e s 5 260-470, 471, 472, 473, 465, 501.16, 515, 516, 520, FOREIGNPATENTS 518, 558, 559, 562, 578, 592, 599, 611, 618, 646, 649,

621,255 Belgium. 268, 326.8, 999

